Humoral immunity is a part of the immune system that involves producing and circulating antibodies. Antibodies are the proteins produced by specialized white blood cells called B cells (B lymphocytes). These antibodies are also known as immunoglobulins.

This immune response is primarily responsible for defending the body against extracellular pathogens, such as bacteria and viruses, that circulate in bodily fluids like blood and lymph. When B cells encounter foreign substances, known as antigens, they undergo a process of activation and differentiation. This process produces plasma cells, which are responsible for secreting antibodies into the bloodstream.

Antibodies play an essential role in humoral immunity because they recognize and bind to specific antigens on the surface of pathogens. The binding can neutralize the pathogens directly or mark them for destruction by other immune system components, such as phagocytes. Additionally, antibodies can activate the complement system.

Humoral immunity is one of the two main branches of the adaptive immune system. The other being cell-mediated immunity, which involves the activation of T cells and focuses more on combating intracellular pathogens. Together, these components provide a comprehensive defense against various infectious agents.

Stages of Humoral Immunity

Humoral immunity involves several stages in response to an infection or the introduction of foreign substances (antigens). These stages collectively contribute to the humoral immune response, crucial for defending the body against extracellular pathogens. These stages include:

1. Antigen Recognition: The process begins when B cells encounter antigens, typically proteins or other molecules on the surface of pathogens. B cells have specific receptors on their surface that can bind to these antigens.
2. Activation of B Cells: Once B cells recognize an antigen that matches their receptors, they become activated. This activation often requires assistance from helper T cells, which release signaling molecules (cytokines) to stimulate the B cell.
3. Proliferation and Differentiation: Activated B cells undergo rapid proliferation, leading to the formation of a clone of identical B cells. Most of these cells differentiate into plasma cells responsible for antibody production.
4. Antibody Production: Plasma cells secrete large quantities of antibodies into the bloodstream. Antibodies are Y-shaped proteins that specifically bind to the antigens on the surface of pathogens, marking them for destruction or neutralization.
5. Antibody Circulation: Antibodies circulate in the bloodstream and other bodily fluids, reaching various tissues to encounter and neutralize pathogens. They can also bind to toxins and prevent them from harming the body.
6. Memory B Cell Formation: Some activated B cells differentiate into memory B cells. These cells “remember” the specific antigen they encountered, providing a quicker and more robust response upon subsequent exposure to the same antigen. This is the basis for immunological memory.
7. Antibody-Mediated Effector Functions: Antibodies carry out several effector functions, including neutralization (blocking the harmful effects of pathogens), opsonization (marking pathogens for destruction by phagocytes), and activation of the complement system (a group of proteins that enhance the immune response). 
8. Resolution and Long-Term Immunity: The immune response gradually decreases as the infection clears. However, memory B cells persist, providing long-term immunity. If the individual encounters the same antigen in the future, the immune system can mount a rapid and effective response.

Types of Humoral immunity with Examples

Humoral immunity can be categorized into two primary types: Active and passive. The basis of this differentiation is how one acquires the immune response. These two types of humoral immunity are essential in defending the body against infections. 

Active immunity offers long-term protection and immunological memory, while passive immunity provides immediate but temporary protection. The choice between active and passive immunity depends on factors such as the nature of the threat, the urgency of protection, and the ability of the individual’s immune system to respond effectively.

Active Humoral Immunity

Active humoral immunity refers to the immune response where the activation of the body’s immune system produces antibodies in response to exposure to antigens. This exposure can be either natural, through infection with a pathogen, or artificial, through vaccination. 

1. Natural Active Humoral Immunity:
   • Example 1: Bacterial Infection: If an individual is infected with a bacterium, such as Streptococcus pneumoniae (causing pneumonia), the immune system recognizes the bacterial antigens. B cells activate to produce antibodies specific to these antigens. This immune response eliminates the bacteria and establishes immunological memory so that the body can mount a quicker and more effective response upon re-exposure.
   • Example 2: Viral Infection: In the case of a viral infection, like influenza, the immune system recognizes viral antigens. B cells activate to produce antibodies that can neutralize the virus and prevent its entry into host cells. These antibodies can also mark the virus for destruction by other immune cells.
2. Artificial Active Humoral Immunity:
   • Example 1: Vaccination against Measles: A person receives a measles vaccine containing weakened or inactivated measles virus antigens. The immune system perceives the antigens as foreign and mounts an immune response. Then, B cells activate to produce antibodies specific to the measles virus. If the vaccinated person is later exposed to the measles virus, their immune system can rapidly produce antibodies, protecting against the infection.
   • Example 2: Hepatitis B Vaccination: Hepatitis B vaccine contains a protein from the surface of the hepatitis B virus. When an individual receives the vaccine, their immune system recognizes the viral protein as foreign and produces antibodies against it. This immune response protects against future infections with the hepatitis B virus.

In both types of active humoral immunity, the key is activating the immune system to produce antibodies and establish immunological memory. The memory allows the immune system to respond more rapidly and effectively upon subsequent exposure to the same pathogen, providing long-lasting protection against specific infections.

Passive Humoral Immunity

Passive humoral immunity involves the transfer of pre-formed antibodies from one individual to another. This transfer can occur naturally or artificially, providing immediate but temporary protection against specific pathogens. 

1. Natural Passive Humoral Immunity:
   • Example 1: Maternal Antibodies: During pregnancy, a pregnant woman can transfer antibodies, primarily IgG, across the placenta to her developing fetus. These maternal antibodies provide the newborn with temporary protection against certain infections during the early months of life. This passive transfer helps protect the infant until its immune system matures and produces antibodies.
   • Example 2: Breast Milk Antibodies: Breast milk contains antibodies, predominantly IgA and other immune components. When a baby is breastfed, it receives these antibodies, providing additional protection against infections in the gastrointestinal and respiratory tracts. This natural passive immunity is crucial for the newborn’s defense against common pathogens.
2. Artificial Passive Humoral Immunity:
   • Example 1: Immune Globulin Administration: Immune globulin, which contains a mixture of antibodies, can be administered to individuals for immediate protection against certain diseases. This can be useful when there is a requirement for rapid immunity, such as exposure to a known pathogen. For example, individuals may receive immune globulin-containing antibodies against hepatitis A or rabies after potential exposure.
   • Example 2: Antivenom Treatment: In cases of snake or spider bites, individuals may receive antivenom, a preparation containing antibodies against the venom. This provides immediate passive immunity, neutralizing the venom and preventing or minimizing the effects of envenomation. The antibodies in antivenom are typically derived from animals that have been immunized with venom.

Passive humoral immunity offers quick but short-lived protection because the transferred antibodies eventually degrade over time, and immunological memory is absent.. In contrast to active immunity, where the individual’s immune system generates antibodies, passive immunity directly transfers antibodies from an external source.

Difference Between Active and Passive Humoral Immunity

Here’s a table summarizing the differences between active and passive humoral immune responses:

These are the primary distinctions between active and passive humoral immune responses.

References

1. Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Chapter 9, The Humoral Immune Response. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10752/
2. Image source: Urry, Lisa A., et al. Campbell Biology. Pearson Higher Education, Inc., 2018.
3. Owen, J. A., Punt, J., & Stranford, S. A. (2013). Immunology (7th ed.). Macmillan Higher Education.

B cells are a type of white blood cell that plays a crucial role in the immune system. Millions of B lymphocytes are generated in the bone marrow daily and exported to the periphery. The rapid and unceasing generation of new B cells occurs in a carefully regulated sequence of events. B-cell development from HSC (hematopoietic stem cell) to mature B cell takes 1 to 2 weeks.

The development of B-cells starts in the bone marrow with the asymmetric division of an HSC. It continues through progressively more differentiated progenitor stages to produce common lymphoid progenitors (CLPs), which can give rise to B or T cells. 

The lymphoid progenitors that remain in the bone marrow become B cells. The developing B cell expresses a precisely calibrated sequence of cell-surface receptors and adhesion molecules on its cell surface as differentiation progresses. 

Some of the signals these receptors receive induce the differentiation of the developing B cell. Others trigger its proliferation at particular development stages, yet others direct its movements within the bone marrow environment. 

Collectively, these signals allow the differentiation of the CLP through the early B-cell stages to form the immature B cell, which leaves the marrow to complete its differentiation in the spleen. The primary function of mature B cells is to secrete antibodies that protect the host against pathogens. 

Maturation of B cell

The maturation of B cells is a tightly regulated process that ensures the development of a diverse B cell repertoire capable of recognizing a wide range of antigens while avoiding harmful self-reactivity. The entire process is essential for the adaptive immune system to respond to pathogens and provide long-term protection effectively.

The maturation of B cells involves a series of stages in the bone marrow and peripheral lymphoid organs. Here is an overview of the maturation process of B cells:

Origin in Bone Marrow

The origination of B cells is from hematopoietic stem cells (HSCs) in the bone marrow. Early B cell precursors, or pro-B cells, undergo immunoglobulin (Ig) gene rearrangement to generate a unique B cell receptor (BCR).

Pre-B Cell Stage

Pro-B cells differentiate into pre-B cells once the successful rearrangement of Ig heavy chain genes (IgH) occurs. Pre-B cells express a pre-BCR consisting of a surrogate light chain and a rearranged heavy chain, allowing further development.

Immature B Cell Stage

Successful rearrangement of Ig light chain genes (IgL) results in a complete BCR. Immature B cells express both IgM and IgD forms of the BCR. At this stage, the B cells undergo a selection process to ensure they do not react strongly to self-antigens. This process is known as adverse selection.

Migration to Secondary Lymphoid Organs

Mature naïve B cells leave the bone marrow and reach secondary lymphoid organs such as lymph nodes and the spleen. Here, the mature B cells interact with antigens for activation and differentiation.

Activation of B cell

B cell activation is an essential step in the humoral immune response, especially for producing antibodies and developing immunological memory. It generally occurs in secondary lymphoid organs such as lymph nodes and spleen. 

The steps involved in the activation of B cells:

1. Recognition of Antigen: B cell activation begins with recognizing specific antigens. Antigens are typically proteins or large molecules present on the surface of pathogens, such as bacteria or viruses.
2. Antigen Binding to B Cell Receptor (BCR): The B cell receptor (BCR) is a membrane-bound antibody molecule on the surface of the B cell. The BCR recognizes and binds to specific antigens. Each B cell has a unique BCR that corresponds to a particular antigen.
3. Internalization of Antigen: Once the BCR binds to the antigen, the antigen-BCR complex is internalized into the B cell through endocytosis.
4. Antigen Presentation: The internalized antigen is processed within the B cell, and fragments of the antigen are presented on the cell surface. These fragments of antigens bind to major histocompatibility complex class II (MHC II) molecules. This complex is then displayed on the B cell surface.
5. Interaction with Helper T Cells: B cells require signals from helper T cells to become fully activated. Helper T cells recognize the antigen-MHC II complex presented by B cells. Co-stimulatory molecules and cytokines facilitate the interaction between the B and helper T cells.
6. Co-stimulation and Activation Signal: Co-stimulatory signals, such as those provided by molecules like CD40 on B cells interacting with CD40 ligands on activated T cells, are essential for B cell activation. The interaction with helper T cells and the receipt of co-stimulatory signals provide the necessary activation signals for the B cell.
7. Clonal Expansion: Activated B cells undergo rapid clonal expansion, resulting in the proliferation of B cell clones specific to the encountered antigen.

Differentiation of B cell

B cell differentiation refers to the process by which activated B cells change their characteristics and functions to become specialized effectors or memory cells. After activation, B cells can differentiate into two primary effector cells: plasma and memory B cells. In summary, B cell differentiation involves transforming activated B cells into specialized effector cells (plasma cells) for immediate immune responses and long-lived memory B cells that confer immunological memory. 

Plasma Cell Differentiation

After activation, some B cells undergo differentiation into plasma cells. Plasma cells are specialized for antibody production. They have an extensive endoplasmic reticulum and Golgi apparatus to support the synthesis and secretion of large quantities of antibodies. The produced antibodies are released into the bloodstream, lymph, or other tissues, where they can neutralize pathogens or mark them for destruction by other immune system components..

Memory B Cell Differentiation

Another subset of activated B cells differentiates into memory B cells. Memory B cells are long-lived cells that remain in the body for an extended period, providing immunological memory. Memory B cells “remember” the specific antigen that triggered their activation. In the event of a subsequent encounter with the same antigen, memory B cells can quickly provide a more rapid and robust immune response.

Immunoglobulin Class Switching

B cells initially express both IgM and IgD forms of the B cell receptor (BCR) on their surface. During differentiation, B cells may undergo class switching, changing the type of immunoglobulin they produce without changing their antigen specificity. This can produce antibodies of different isotypes, such as IgG, IgA, or IgE, each with distinct effector functions.

Affinity Maturation

B cells can undergo affinity maturation during an immune response, particularly in the germinal centers of secondary lymphoid organs. Affinity maturation involves selecting B cells with higher affinity BCRs through somatic hypermutation and the subsequent survival of B cells with improved antigen-binding capabilities.

Germinal Center Reaction

The germinal center reaction is critical in secondary lymphoid organs during B cell activation. Within germinal centers, B cells undergo rapid proliferation, somatic hypermutation, and selection, leading to the generation of high-affinity antibody-producing cells and memory B cells.

References

1. LeBien, T. W., & Tedder, T. F. (2008). B lymphocytes: how they develop and function. Blood, 112(5), 1570–1580. https://doi.org/10.1182/blood-2008-02-078071
2. Althwaiqeb SA, Bordoni B. Histology, B Cell Lymphocyte. [Updated 2023 May 29]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560905/ 
3. Owen, J. A., Punt, J., & Stranford, S. A. (2013). Immunology (7th ed.). Macmillan Higher Education.

T-cell activation is essential in the immune response, specifically in the adaptive immune system. T cells, a type of lymphocyte, play a central role in coordinating and executing immune responses against specific pathogens.

Activation of mature peripheral T cells begins with the interaction of the T-cell receptor (TCR) with an antigenic peptide displayed in the groove of an MHC molecule. Although the TCR governs the TCR governs, the specificity of ow avidity necessitates the involvement of coreceptors and other accessory membrane molecules that strengthen the TCR-antigen-MHC interaction and transduce the activating signal. 

Activation leads to the differentiation of T cells into various types of effector and memory T cells. Because the vast majority of thymocytes and peripheral T cells express the T-cell receptor rather than the T-cell receptor

Steps of T cell activation

The activation process involves several steps and is tightly regulated to ensure an effective and targeted immune response. 

Antigen Recognition

T-cell activation begins with the recognition of specific antigens. Antigens are fragments of proteins derived from pathogens (such as viruses or bacteria) or abnormal cells. The T cell recognizes antigen-presenting cells (APCs), primarily dendritic cells, macrophages, and B cells.

Antigen Presentation

APCs can process and present antigens on their cell surface in corporation with major histocompatibility complex (MHC) molecules. MHC class II molecules present antigens to CD4+ T cells (helper T cells), while MHC class I molecules present antigens to CD8+ T cells (cytotoxic T cells).

T Cell Receptor (TCR) Engagement

T cells express TCRs on their surface, interacting with the presented antigen-MHC complex on APCs. This interaction is particular, and the binding of the TCR to the antigen-MHC complex is a critical event in T cell activation.

Co-stimulation

In addition to TCR engagement, co-stimulatory signals are required for full T-cell activation. Co-stimulatory molecules, such as CD28 on T cells and B7 on APCs, interact to provide the necessary secondary signals. This helps prevent inappropriate activation and ensures T cells respond only to genuine threats.

Signal Transduction

The binding of the TCR to the antigen-MHC complex, along with co-stimulatory signals, initiates intracellular signaling pathways within the T cell. This activates various proteins and transcription factors, including those involved in cytokine production and cell proliferation.

Clonal Expansion

Activated T cells undergo clonal expansion, rapidly expanding to generate a large population of effector T cells. This expanded T cell population includes both effector T cells, which carry out immune functions, and memory T cells, which provide long-term immunity.

Differentiation into Effector T Cells

CD4+ T cells differentiate into various effector T cell subsets, such as Th1, Th2, Th17, or regulatory T cells (Tregs), depending on the cytokine microenvironment. CD8+ T cells differentiate into cytotoxic T cells capable of directly killing infected or abnormal cells.

Migration to Site of Infection

Activated T cells, both CD4+ and CD8+, migrate to the site of infection or inflammation through the bloodstream. Chemokines and adhesion molecules facilitate their homing to specific tissues.

Effector Functions

Effector T cells carry out their functions, including activating other immune cells, producing cytokines, or directly killing infected or abnormal cells. This phase is essential for eliminating the threat and resolving the infection.

Contraction and Memory Formation

After clearing the pathogen, most effector T cells undergo apoptosis (programmed cell death), reducing the T cell population. However, a subset of T cells transforms into memory cells, providing long-lasting immunity and faster response upon re-exposure to the same antigen. 

Biological Pathways for T-cell Activation

When T cells recognize antigens and costimulators, they express proteins involved in proliferation, differentiation, and effector functions. Naive T cells that have not interacted with antigens (so-called resting cells) have a low level of protein synthesis. 

Within minutes of antigen recognition, new gene transcription and protein synthesis are seen in the activated T cells. The biochemical pathways that link antigen recognition with T-cell responses consist of activating enzymes, recruiting adapter proteins, and producing active transcription factors. 

Generation of Intracellular Signals

Several transmembrane signaling proteins, including the CD3 and ζ chains, are associated with the TCR. CD3 and ζ contain tyrosine-rich motifs, called immuno-receptor tyrosine-based activation motifs (ITAMs), critical for signaling. Once it is activated. Lck phosphorylates tyrosine residues contained within the lTAMs of the ζ and CD3 proteins. The phosphorylated ITAMs of the ζ chain become docking sites for a tyrosine kinase called ZAP-70 (ζ-associated protein of 70 kD), which is also phosphorylated by Lck and made enzymatically active. The active ZAP-70 then phosphorylates various adapter proteins and enzymes, which assemble near the TCR complex and mediate additional signaling events.

Signaling Pathways 

Two major signaling pathways linked to ζ chain phosphorylation and ZAP-70 are the calcium-NFAT and the Ras/Rac kinase pathways. 

Calcium-NFAT Pathways

NFAT (Nuclear factor of activated T cells) is a transcription factor whose activation is dependent on Ca²⁺ ions. The calcium-NFAT pathway is initiated by ZAP-70-mediated phosphorylation and activation of an enzyme called phospholipase C (PLC), which catalyzes the hydrolysis of plasma membrane inositol phospholipids. One byproduct of PLC-mediated phospholipid breakdown, called inositol 1,4,5- triphosphate (IP₃), stimulates the release of Ca²⁺ ions from intracellular stores. At the same time, signals from the TCR complex lead to the influx of extracellular Ca²⁺ in the cell. Cytoplasmic Ca²⁺ binds a calmodulin protein, and the Ca2+-calmodulin complex activates a phosphatase called calcineurin. This enzyme removes phosphates from a nuclear factor of activated T cells, called an inactive cytosolic transcription factor.

Once dephosphorylated, NFAT can migrate into the nucleus, where it binds to the promoters of several genes, activating them. A drug called cyclosporin binds to and inhibits calcineurin’s activity, thus inhibiting the production of cytokines by T cells. This agent is widely used as an immunosuppressive drug to prevent graft rejection; its advent has been one of the significant factors in the success of organ transplantation in the past decade. 

Ras/Rac-MAP Kinase Pathways

The Ras/Rac-MAP kinase pathways include the guanosine diphosphate (GTP) binding Ras and Rac proteins, which are biologically active when bound to GTP, several adapter proteins, and a cascade of enzymes that eventually activate one of a family of mitogen-activated protein (MAP) kinases. The pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adapter proteins at the plasma membrane, leading to the recruitment of Ras or Rac and their activation by exchange of GTP and guanosine diphosphate (GDP). Both Ras-GTP and Rac-GTP initiate different enzyme cascades that leado the activation of distinct MAP kinases. The terminal MAP kinases in these pathways, called extracellular signal-regulated kinase (ERK) and cJun amino(N)-terminal kinase WK), promote the expression of a protein called c-Fa and the phosphorylation of another protein called c-Jun. C-Fos and phosphorylated c-Jun combine to form the active transcription factor AP-1 (activating protein-1 ). which enhances the transcription of several T-cell genes.

Other Biochemical Events

Other biochemical events involved in TCR signaling include the serine-threonine kinase called protein kinase C (PKC), which activates the transcription factor nuclear factor-kb (NF-κB). PKC is activated by diacylglycerol, which, like IP₃, is generated by phospholipase C-mediated hydrolysis of membrane inositol lipids. A T cell-specific PKC isoform, PKC-θ, is linked to NF-κB activation. NFκB exists in the cytoplasm of resting T cells in an inactive form, which binds to an IKB inhibitor. TCR signals generated by antigen recognition lead to phosphorylation and dissociation of the NF-κB-bound inhibitor. As a result, NF-κB is released and can move to the nucleus, activating the transcription of several genes. 

The transcription factor, NFAT, AP-I, and NF-κB, stimulate transcription. After that production of cytokine receptors, cell cycle inducers, and effector molecules such as CD40L occurs. All the signals are initiated by antigen recognition because binding the TCR and coreceptors to antigen (peptide-MHC complexes) is necessary to assemble the signaling molecules and initiate their enzymatic activity. 

The recognition of costimulators, such as B7 molecules, by their receptor (i.e., CD28) is essential for complete T-cell responses. The signals transduced by CD28 on binding to B7 costimulators are even less defined than TCR-triggered signals. CD28 engagement amplifies TCR signals, or CD28 initiates a distinct set of signals that complement TCR signals. These possibilities, of course, are not mutually exclusive. 

References

1. Abbas, A. K., & Lichtman, A. H. (2006). Basic immunology: Functions and disorders of the immune system. Elsevier Saunders. 
2. Kuby Immunology, 8th Edition

Multicellular organisms, including plants, vertebrates, and invertebrates, have an intrinsic method of defending themselves against microbial infections. Since these methods are always present, ready to recognize and eliminate microbes, they are called innate immune systems or (natural or native immunity). 

The innate immune system consists of different components. The only commonality is that they recognize and respond to microbes but do not react against non-microbial substances. Host cells damaged by microbes also trigger this type of immunity. 

Innate immunity differs from adaptive immunity, where adaptation occurs after stimulation to encounter with microbes before it can be effective. Likewise, both microbes and non-microbial antigens can trigger adaptive immunity.  

Components of Innate Immune System

The innate immune system consists of epithelia, which provide barriers to infection, cells in the circulation and tissues, and several plasma proteins. These components play different but complementary roles in blocking the entry of microbes and eliminating microbes that enter the host’s tissues. 

Epithelial Barriers

The continuous epithelia provide physical and chemical barriers against infection. It also protects the standard portals of entry of microbes, namely, the skin, gastrointestinal, and respiratory tract. The three significant interfaces between the body and the external environment are the skin, the gastrointestinal tract, and the respiratory tract.

Microbes may enter hosts from the external environment through these interfaces by physical contact. ingestion, and breathing. All three portals of entry are lined by continuous epithelia that physically interfere with the entry of microbes. 

Epithelial cells also produce peptide antibiotics that kill bacteria. In addition, epithelia contain a type of lymphocyte called intraepithelial lymphocyte, belonging to the T cell lineage. However, this lymphocyte expresses antigen receptors of limited diversity. Intraepithelial lymphocytes presumably serve as sentinels against infectious agents that attempt to breach the epithelia. However, the specificity and functions of these cells still need to be better understood. 

A population of B lymphocytes. B-1 cells resemble intraepithelial T cells in the limited diversity of their antigen receptors. B-1 cells are not present in epithelia but mainly in the peritoneal cavity, where they may respond to microbes and microbial toxins that pass through the walls of the intestine. Most of the circulating IgM antibodies found in the blood of normal individuals, called natural antibodies, are the products of B-1 cells, and many of these antibodies are specific for carbohydrates present in the cell walls of many bacteria.

Phagocytes: Neutrophils and Monocytes/Macrophages

Neutrophils and monocytes are two types of circulating phagocytes recruited to the site of infection, where they recognize and ingest microbes for intracellular killing.

Neutrophils and macrophages recognize microbes in the blood and extravascular tissues by surface receptors specific to microbial products. Several types of receptors are specific for different structures or patterns frequently found on microbial molecules. 

Neutrophils and macrophages express receptors that recognize other microbial structures and promote phagocytosis and killing of the microbes. These receptors include one that recognizes N-formylmethionine-containing peptides (produced by microbes but not host cells), mannose receptors (mentioned earlier), integrins (mainly one called Mac-1), and scavenger receptors (specific for several pathogen and host molecules). 

Neutrophils or polymorphonuclear leukocytes or PMNs

These are the most abundant leukocytes in the blood, numbering 4000 to 10,000 per mm³. In response to infections, neutrophil production from the bone marrow increases rapidly, and their number may rise to 20,000 per mm³ of blood. Cytokines, known as colony-stimulating factors, act on bone marrow stems in response to infections and stimulate the production of neutrophils; neutrophils are the first cell type to respond to most bacterial and fungal infections. They ingest microbes in the circulation and enter the sites of infection, where they also ingest microbes and die after a few hours.

Monocytes/Macrophages 

These are less abundant than neutrophils, numbering 500 to 1000 per mm³ of blood. They, too, ingest microbes in the blood and tissues. Unlike neutrophils, monocytes that enter extravascular tissues survive in these sites for extended periods; in the tissues, these monocytes differentiate into cells called macrophages. Blood monocytes and tissue macrophages are two stages of the same cell lineage, often called the mononuclear phagocyte system. Resident macrophages are present in connective tissues and every organ in the body, serving the same function as mononuclear phagocytes newly recruited from the circulation.

Macrophages also express cytokine receptors, such as interferon-y (IFN-y), produced during innate and adaptive immune responses. 

The process of coating microbes for efficient recognition by phagocytes is called opsonization. The recognition of microbes by neutrophils and macrophages leads to phagocytosis of the microbes and activation of the phagocytes to kill the ingested microbes. 

Phagocytosis is a process in which the phagocyte extends its plasma membrane around the recognized microbes; the membrane closes up. It pinches off, and the particle internalizes in a membrane-bound vesicle called a phagosome. The phagosomes and lysosomes fuse to form phagolysosomes. At the same time, phagocyte receptors bind the microbe and ingest it. The receptors deliver signals that activate several enzymes in the phagolysosomes.

One of these enzymes, phagocyte oxidase, converts molecular oxygen into superoxide anion and free radicals. The enzyme-inducible nitric oxide synthase catalyzes arginine to nitric oxide (NO), a microbicidal substance. The third set of enzymes are lysosomal proteases, which break down microbial proteins.

In addition to killing phagocytosed microbes, macrophages perform several functions that play essential roles in defense against infections. Macrophages produce cytokines that are important mediators of host defense. These secrete growth factors and enzymes to remodel injured tissue and replace it with connective tissue. Macrophages also stimulate T lymphocytes and respond to the products of T cells; these reactions are important in cell-mediated immunity.  

Natural Killer (NK) Cells

These cells are a class of lymphocytes that respond to intracellular microbes by killing infected cells and producing macrophage-activating cytokine, IFN-gamma. Natural killer cells comprise about 10% of the lymphocytes in the blood and peripheral lymphoid organs. These cells contain abundant cytoplasmic granules and express characteristic surface markers, but they do not express immunoglobulins or T cell receptors, the antigen receptors of B and T lymphocytes, respectively. NK cells recognize host cells that have been altered by microbial infection. 

Two prominent families of NK cell inhibitory receptors are the killer cell immunoglobulin-like receptors (KIRs), so-called because they share structural homology to immunoglobulin molecules, and receptors consisting of a protein called CD94 and a lectin submit called NKG2. Both families of inhibitory receptors contain structural motifs called immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains, which become phosphorylated on tyrosine residues when the receptors bind MHC I molecules. 

When NK cells activate, they respond in two ways. First, activation triggers the discharge of proteins in the NK cells’ cytoplasmic granules toward the infected cells. These NK cell granule proteins include molecules that make holes in the plasma membrane of the infected cells and other molecules that enter the infected cells and activate enzymes that induce apoptotic death.

Second, activated NK cells synthesize and secrete the cytokine IFN-y. IFN-y activates macrophages to become more active at killing phagocytosed microbes. Thus, NK cells and macrophages function cooperatively to eliminate intracellular microbes: macrophages -st microbes and produce IL-12. IL-12 activates NK cells to secrete IFN-y and IFN-y, which, in turn, activates the macrophages to kill the ingested microbes.

Thus, hosts and microbes are engaged in a constant evolutionary struggle:

• The host uses CTLs to recognize MHC-displayed viral antigens.
• Viruses shut off MHC expression.
• NK cells have evolved to respond to the absence of MHC molecules.

Whether the host or the microbe wins this kind of evolutionary struggle, of course, determines the outcome of the infection. 

Cytokines of Innate Immunity

Macrophages and other cells produce proteins called cytokines in response to microbes mediating many of innate immunity’s cellular reactions. Cytokines are soluble proteins that mediate immune and inflammatory reactions and are responsible for communications between leukocytes and other cells.

The Complement System

The complement system is a group of circulating and membrane-associated proteins essential in defense against microbes. Many complement proteins are proteolytic enzymes, and complement activation involves the sequential activation of these enzymes, sometimes called an enzymatic cascade.

This cascade may be activated by one of three pathways. The alternative pathway is triggered when some complement proteins are activated on microbial surfaces, which is impossible to control because microbes lack complement regulatory proteins. This pathway is a component of innate immunity.

Antibodies binding to microbes or other antigens triggers the classical pathway. Thus, it is a component of the humoral immunity. 

The lectin pathway activates when mannose-binding lectin, a plasma protein, binds to terminal mannose residues on the surface glycoproteins of microbes. This lectin activates proteins of the classical pathway. However, the initiation occurs without antibodies. Thus, it is a component of innate immunity.

Other Plasma Proteins of Innate Immunity 

Several circulating proteins, including complement proteins, defend against infections. Plasma mannose-binding lectin (MBL) is a protein that recognizes microbial carbohydrates and can coat microbes for phagocytosis or activate the complement cascade by the lectin pathway. 

Surfactant proteins in the lung protect the airways from infection. C-reactive protein (CRP) binds to phosphorylcholine on microbes and coats the microbes for phagocytosis by macrophages, which express a receptor for CRP. 

The circulating levels of many of these plasma proteins increase rapidly after infection. This protective response is called the acute phase response to infection. 

Innate immune responses to different microbes may vary and are designed to eliminate these microbes in the best way possible. Phagocytes, the complement system, and acute phase proteins combat extracellular bacteria and fungi. Defense against intracellular bacteria and viruses is mediated by phagocytes and NK cells. The cytokines provides the communication between the phagocytes and NK cells. 

Evasion of Innate Immunity by Microbes 

Pathogenic microbes have evolved to resist the mechanisms of innate immunity and are thus able to enter and colonize their hosts. Some intracellular bacteria resist destruction inside phagocytes. Listeria monocytogenes produces a protein that enables it to escape from phagocytic vesicles. Then these enter the cytoplasm of infected cells. Here it is no longer susceptible to reactive oxygen intermediates and nitric oxide (produced mainly in phagolysosomes). 

The cell wall of mycobacteria contains a lipid that inhibits the fusion of vesicles containing ingested bacteria with lysosomes. Other microbes have cell walls that are resistant to the actions of complement proteins.

References

1. Abbas, A. K., & Lichtman, A. H. (2006). Basic immunology: Functions and disorders of the immune system. Elsevier Saunders. 
2. Aristizábal B, González Á. Innate immune system. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 2. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459455/

Hypersensitivity refers to an exaggerated or unnecessary reaction produced by the host immune system. It is an immunological dysfunction, mainly targeted at innocuous antigens with consequent tissue damage.

The human immune system protects body from damage by fighting invasive substances and infections. Sometimes, however, it can ‘overreact,’ identifying harmless substances as harmful, which causes undesirable consequences. This is called a hypersensitivity response.

Hypersensitivity reactions include allergies and autoimmune diseases. Exogenous substances cause allergies, whereas endogenous substances cause autoimmune disorders in sensitive individuals. Sometimes, the term allergy is used to explain hypersensitivity. However, these are different terms. Allergies are signs and symptoms, but hypersensitivity reaction is an immunological process in the body. Certain types of hypersensitivity reactions show an allergy (mainly type I reactions) in response to exogenous (and harmless) antigens.

The symptomatic reaction only occurs in sensitized individuals, i.e., must have had at least one prior asymptomatic contact with the offending antigen.

Classification of Hypersensitivity Reactions

The human body shows different types of hypersensitivity reactions, depending on the antigen a person has exposure to and how the body responds to it.

Historically hypersensitivity was divided on a time basis into immediate and delayed reactions. Generally, quick response develops in less than 24 hours, and delayed reaction develops within 24-48 hours.

However, the most popular classification is Coombs and Gell’s classification. This was given in 1963, which classifies hypersensitivity into four different types. Each type differs based on the antigen type the body identifies, the kind of host immune response, or how quick the response is.

Type I, II, and III are antibody-dependent and immediate reactions, whereas type IV is antibody-independent and has delayed response.

Type I Hypersensitivity

Type I hypersensitivity or allergy is the most common immune disorder. It is also known as an immediate or anaphylactic hypersensitivity reaction. The reaction usually takes 15-30 minutes from the time of exposure to the allergen (antigen), but sometimes, delayed onset (10-12 hours) can be seen.

The initial introduction of an antigen (or an allergen) produces IgE response. Cross-linking of IgE with sensitized cells ultimately leads to release of mediators like histamine, leukotriends, and prostagladins causing widespread vasodilation, bronchoconstriction, and increased permeability of vascular endothelium.  

Read more about mechanism of Type I hypersensitivity 

The reaction affects the skin, eyes, nasopharynx, and gastrointestinal tract. The response may be systemic or local, and the reaction may cause a range of symptoms from minor inconvenience to death. Examples of type I hypersensitivity reactions are anaphylaxis, food allergy, asthma, allergic conditions of rhinitis, and conjunctivitis.

Type II Hypersensitivity

Type II hypersensitivity reactions are cytotoxic and may affect a variety of organs and tissue. The antigens usually are endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity. Thus, type II hypersensitivity reactions may occur in response to host cells (i.e., autoimmune) or non-self cells, as in blood transfusion reactions. Type II reactions are antibody-mediated. IgG or IgM antibodies are involved, targeting antigens on cell surfaces.

Type II hypersensitivity can lead to tissue damage by three main mechanisms. 

1. Antibody and complement-mediated destruction
2. ADCC(Antibody-Dependent Cell-Mediated Cytotoxicity) and
3. Target cell dysfunction

Read more about Type II hypersensitivity mechanism here 

Type II hypersensitivity reactions include newborns’ hemolytic disease, Graves disease, Myasthenia gravis, blood transfusion reaction, and Goodpasture syndrome.

Type III Hypersensitivity

This is caused by antigen-antibody complex or immune complex. The response may be the pathogenic mechanism of diseases caused by many microorganisms. These can deposit in capillaries or joints and trigger inflammation if not eliminated.

The reaction occurs 3-10 hours after exposure. Mainly, IgG antibodies are involved in the response. However, IgM antibodies are also applied.

Read more about the mechanism of Type III hypersensitivity here

Localized reactions like Arthus reaction, farmer’s lung disease, rheumatoid arthritis, systemic reactions like serum sickness, and systemic lupus erythematosus are examples of type III hypersensitivity reactions.

Type II is distinguished from type III by the location of the antigens. In type II, cell-bound antigens are involved, whereas in type III, antigens are soluble.

Type IV Hypersensitivity

Type IV hypersensitivity reactions are also called delayed-type hypersensitivity (DTH), as response starts only after 24 to 72 hours. The reaction takes longer than all other types because of the time required to recruit cells to the exposure site.

Unlike other types, it is a cell-mediated hypersensitivity reaction. Antigen-specific activated T-cells mediate it. 

Read more about the mechanism of Type IV hypersensitivity here. 

Transplant rejection, granuloma, contact dermatitis, tuberculin reaction, Multiple sclerosis, insulin-dependent diabetes mellitus.

Different types of hypersensitivity reactions can be summarized in the following table:

Diagnosis

Diagnosis of hypersensitivity reactions is based on symptoms, personal history, and medical records. Laboratory findings of blood, urine, imaging, allergic skin test, biopsy or culture, liver, and kidney function tests, TSH and TFT, etc. are carried out depending on the nature of the disease and hypersensitivity types.

Type I, II, and III are antibody-mediated, and their clinical features can overlap. In such a case, differential diagnosis is necessary.

In type I reaction, the diagnosis is primarily based on the association of antigen exposure to clinical manifestations, such as fever, arthritis, and rash. Physical examination, in addition to IgE level in serum and allergy tests, is performed. 

Diagnosis of type II reaction includes the detection of circulating antibodies against the tissue involved and the presence of antibodies and complement in the lesion (biopsy) by immunofluorescence.Coombs test is done in transfusion reaction and anemia. Pregnancy history is required to diagnose erythroblastosis fetalis; ultrasound, fetal laboratory test, and maternal antibody tests are performed. In rheumatoid arthritis, CRP, ASO, and ESR are performed. Diagnosis tests in vivo include delayed cutaneous reactions (e.g., manteaux test in type IV hypersensitivity reactions).

Management and control

The first and most important way of minimizing hypersensitivity reactions is finding out the cause and eliminating or avoiding it. If it is impossible, one can follow treatment procedures to reduce the risks. Such reactions are treated according to the symptoms and diseases. Some of the measures are listed below:

• Removal of the offending agent 
• Reviewing the drug allergy list and related side effects for patients 
• Use of immunotherapy and immunosuppressive drugs in autoimmune conditions or in hypersensitivity reactions, under the supervision of a specialist. 
• Rapid cessation of transfusion, and supportive care in case of blood transfusion reaction
• Use of humanized or genetically engineered antibodies instead of antibodies from animal origin.

References

• Hypersensitivity reactions – knowledge @ amboss. ambossIcon. (n.d.). Retrieved November 9, 2022, from https://www.amboss.com/us/knowledge/Hypersensitivity_reactions/
• Basu S, Banik BK (2018) Hypersensitivity: An Overview. Immunol Curr Res 2: 105.https://www.omicsonline.org/open-access/hypersensitivity-an-overview-105371.html
• Momtazmanesh S & Rezaei N (2022). Encyclopedia of Infection and Immunity. www.sciencedirect.com/topics/medicine-and-dentistry/hypersensitivity
• Speller J (2022). Hypersensitivity reactions: TeachMe Physiology https://teachmephysiology.com/immune-system/immune-responses/hypersensitivity-reactions/

Allergies and autoimmunity are conditions related to the immune system. They occur when antigens activate immune cells.

Allergies and autoimmune diseases follow a similar developmental way, though their presentation is often quite different. Allergic reactions occur when the immune system reacts to foreign environmental substances. With allergies, the invaders are otherwise harmless environmental triggers. On the other hand, autoimmunity is a system of responses from the immune system against the body’s healthy cells and tissues. With an autoimmune disease, our immune system mistakenly identifies the host’s cells for destruction. The brief descriptions of allergies and autoimmune diseases, their similarities and differences are given below:

What are allergies?

Allergies are a type of hypersensitivity reactions mediated by immunoglobulin E (IgE). Allergies are not related to any diseases or infections. These can be observed in various body parts; the effect is mainly seen on the skin and mucus membrane. The immune system recognizes innocuous non-self antigens (e.g., proteins in peanuts) and responds against them. The human body may be sensitive to such specific particles found in the environment. Such particles are called allergens. Allergens are the antigens producing abnormally exaggerated immune responses.

Common allergens are dust, pollen, feathers, latex, pet dander, mites, and even food particles, like peanuts. 

When the body encounters an allergen, antibodies called immunoglobulin E (IgE) are produced in its response. It is followed by the release of chemicals such as histamine and serotonin.

Sneezing, coughing, running nose, red eyes, itchy rashes, or difficulty breathing and swallowing can be allergy symptoms. Allergy to at least one allergen is common throughout the world. However, in recent times more people are prone to allergies due to modern and unhealthy lifestyles, as they have low immunity and high environmental sensitivity.

What are Autoimmunities?

The system of immune responses of an organism against its healthy cells and tissues is autoimmunity. Diseases that occur because of such reactions are called autoimmune diseases. In autoimmunity, the immune system attacks cells expressing self-antigens. Such self-reactive immune cells produce autoantibodies. Thus, autoimmunity is an overburdened immune system causing systemic inflammation.

The higher classes of vertebrates can recognize foreign antigens. Their immune system can distinguish perfectly between their cells and foreign organisms. But, sometimes, the body attacks its cells and tissues due to genetic defects, environmental factors, or some other unknown cause. This results in autoimmune diseases. An imbalance in T cell function (which produces and suppresses the immune response) helps to develop autoimmune diseases.

Rheumatoid arthritis (RA), Graves’ disease, and polymyositis are common examples of autoimmune diseases.

In some cases, allergies trigger autoimmune diseases. One of the examples is the gluten-thyroid connection, where antibodies against it attack thyroid tissue.

Similarities

• Both of them have symptoms of general fatigue and sickness.
• Itching can be a common symptom of both.
• In the higher immune response, allergy and autoimmune disease result in some redness or swelling.
• Hypersensitivity can cause both allergies and autoimmunity.

Differences between allergies and autoimmunity

References

• byjus.com/biology/allergies-autoimmunity/
• August et. al. Autoimmunity and Allergy: Session 7 https://www.ibiology.org/sessions/session-7-autoimmunity-and-allergy/
• https://centrespringmd.com/do-allergies-trigger-autoimmune-disease/