Humoral Adaptive Immunity

Humoral adaptive immunity is an integral part of the adaptive immune system, which mounts a highly specific defense against pathogens but takes a longer time to respond (compared to the innate immune system Innate immune system Innate immunity, the 1st protective layer of defense, is a system that recognizes threatening microbes, distinguishes self-tissues from pathogens, and subsequently eliminates the foreign invaders. The response is nonspecific and uses different layers of protection: barriers such as the skin, pattern recognition receptors (PRRs) as well as circulating proteins, and immune cells that help eliminate the microbe. Cells of the Innate Immune System). Humoral immunity is the arm Arm The arm, or "upper arm" in common usage, is the region of the upper limb that extends from the shoulder to the elbow joint and connects inferiorly to the forearm through the cubital fossa. It is divided into 2 fascial compartments (anterior and posterior). Arm of the immune system protecting the extracellular fluids of the lymphatics (lymph), interstitium, and circulatory system (plasma) from microbial contamination mediated through soluble molecules. The B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells play a major role, producing antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins or immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins. Arising from the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells originate from the common lymphoid progenitor and undergo stages to assemble the B cell receptor. To become fully functional, activation follows, and this can be T cell–dependent (which produces memory cells) or T cell–independent (producing a short-lived response). When activated, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells go through processes enhancing antigen affinity, class switching, and differentiation to plasma cells and memory cells. Plasma cells produce the antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, while memory B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells respond to reinfection. There are different immunoglobulin isotypes, generally providing immune protection through complement activation, opsonization, neutralization of toxins or viruses, and induction of cell lysis.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview

Immune system: definition

The immune system provides defense (immunity) against invading pathogens ranging from viruses to parasites. The components of the system are interconnected by blood and the lymphatic circulation.

2 lines of defense (that overlap):

  • Innate immunity (which is nonspecific) 
  • Adaptive immunity (based on specific antigen recognition):
    • Cell-mediated immunity: adaptive response in the cells/tissues involving the T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
    • Humoral immunity: adaptive response in the fluids (humors) involving B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins

Innate vs. adaptive immunity

Table: Innate versus adaptive immunity
Innate immunity Adaptive immunity
Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics Germline encoded Gene rearrangements involved in lymphocyte development
Immune response Nonspecific Highly specific
Timing of response Immediate (minutes to hours) Develops over a longer period of time
Memory response Without memory response With memory response, which responds quickly upon recognition of antigen
Recognition of pathogen Pattern recognition receptors (PRRs) such as TLRs recognize pathogen-associated molecular patterns (PAMPs).
  • Memory cells (T and B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells)
  • Activated B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells
Components
  • Chemical and biological barriers (e.g., gastric acid, vaginal flora)
  • Anatomical barriers (e.g., skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)
  • Cells (e.g., granulocytes)
  • Secreted proteins:
    • Enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (e.g., lysozyme)
    • Other PRRs (e.g., antimicrobial peptides (AMPs))
    • Cytokines*
    • Complement* system
  • Cell-mediated immunity: T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
  • Humoral immunity: B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
*These mediators also have roles in adaptive immunity.

Components of the Adaptive Immune System

Responding to microbial invaders is the responsibility of the immune system. Often, the innate immune system Innate immune system Innate immunity, the 1st protective layer of defense, is a system that recognizes threatening microbes, distinguishes self-tissues from pathogens, and subsequently eliminates the foreign invaders. The response is nonspecific and uses different layers of protection: barriers such as the skin, pattern recognition receptors (PRRs) as well as circulating proteins, and immune cells that help eliminate the microbe. Cells of the Innate Immune System has the capability to contain the pathogens, but invaders have evolved means to evade innate immunity. The next line of defense is the adaptive immune system.

Adaptive immune system: definition

  • Composed of lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes (T helper cells, cytotoxic T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells) and secreted proteins ( antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins produced by B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells)
  • Functionality takes days, but once engaged, repeat encounters with the offending agent elicits a faster response.
  • The components, B and T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, have:
    • Diversity: respond to millions of antigens
    • Specificity: immune response tailored to the specific antigen
    • Memory: can respond many years later

Cell-mediated immunity

  • Primary effectors: T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells
    • CD4+ T (helper) cells: Different subsets perform multiple functions (including cytokine production, activation of macrophages).
    • CD8+ T (cytotoxic) cells: defend against intracellular bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview and viruses via destruction of infected cells. 
    • Memory T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells: respond to antigen reexposure
  • Other components:
    • T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells are dependent on cytokines (soluble proteins released by different cells, which play overlapping roles in both innate and adaptive immunity).
    • Several cells (dendritic cells, macrophages) in the innate immune system Innate immune system Innate immunity, the 1st protective layer of defense, is a system that recognizes threatening microbes, distinguishes self-tissues from pathogens, and subsequently eliminates the foreign invaders. The response is nonspecific and uses different layers of protection: barriers such as the skin, pattern recognition receptors (PRRs) as well as circulating proteins, and immune cells that help eliminate the microbe. Cells of the Innate Immune System present antigens to the T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells.

Humoral adaptive immunity

  • Antibody-mediated immunity
  • B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells:
    • Differentiate into plasma cells, producing antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (through the help of T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells)
    • Differentiate into memory cells, briskly responding to reinfection
    • Act as antigen-presenting cells to T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells (expressing MHC II)
  • Antibodies, along with complement, help the cells of the innate system against extracellular, encapsulated bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview.
  • Antibodies can neutralize toxins, such as tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus toxin, and viruses.

Development of B Cells

B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells

  • Arise from the common lymphoid progenitor 
  • In stages, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells develop in the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow:
    • Gene rearrangements of the segments of the Ig molecule
    • Assembly of a mature B cell receptor (BCR), which Ig is a part of
  • A mature naive B cell with a BCR:
    • Exits the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow, migrating to secondary lymphoid organs
    • Expresses IgM and IgD once within the secondary lymphoid tissues

B cell receptor (BCR)

  • Consists of the Ig molecule and a signaling molecule
  • The Ig molecule is anchored to the cell surface:
    • Has heavy chains (μ, δ, γ, α, or ε) disulfide-linked to light chains (κ or λ)
    • Has a constant and variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables region (where the antigen binds)
  • Gene rearrangements (uniting different gene segments) within B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells are needed to assemble the Ig molecule.
  • This process also produces a repertoire of diverse B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells and creates protection against different kinds of infections.
B-cell receptor (bcr)

The B cell receptor (BCR) consists of the Ig molecule and the signaling molecule:
Ig contains 2 identical heavy chains and 2 identical light chains linked by a disulfide bridge. The membrane-bound Ig is anchored to the cell surface.

Image:“Figure 42 02 06” by OpenStax. License: CC BY 4.0

B cell activation

Steps needed for the B cell to function:

  • 2 signals needed:
    • Signal 1: antigen to the BCR (the more BCRs cross-linked by the antigen, the stronger the signal)
    • Signal 2: 
      • Inflammatory sources or antigens present a threat to the host.
      • Without signal 2, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells do not get activated (this prevents inadvertent activation by harmless antigens).
  • T cell–dependent activation:
    • Antigen binds to BCR → endocytosed and degraded
    • The degraded antigen attaches to surface MHC II molecules.
    • The B cell circulates through lymph nodes → encounters activated CD4+ T follicular helper (Tfh) cells 
    • Antigen–MHC II complex is recognized by Tfh cells → B cell is activated → B cell proliferation
  • T cell-independent activation:
    • Activation does not always need the help of T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells.
    • Some antigens, like the polysaccharides of a bacterial cell (e.g., Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae and Haemophilus Haemophilus Haemophilus is a genus of Gram-negative coccobacilli, all of whose strains require at least 1 of 2 factors for growth (factor V [NAD] and factor X [heme]); therefore, it is most often isolated on chocolate agar, which can supply both factors. The pathogenic species are H. influenzae and H. ducreyi. Haemophilus influenzae), can directly stimulate B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells.
    • Short-lived responses, with mostly IgM production (no memory)
  • To produce a functional differentiated B cell after activation by an antigen, processes that take place include:
    • Proliferation
    • Affinity maturation:
      • Fine-tuning of the antibody affinity to the antigen
      • Achieved by somatic hypermutation (programmed mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations involving Ig heavy and light chain genes)
      • Produces BCR with enhanced ability to recognize and bind antigen
    • Class switching:
      • Heavy chain determines the Ig class (IgM, IgG, IgE, IgA, IgD).
      • Influenced by cytokines
    • Differentiation into plasma or memory cell
Differentiation stages of the b cell

Differentiation stages of the B cell:
In antigen-independent stages, B cell production starts with the hematopoietic stem cell (HSC), which becomes a common lymphoid progenitor (CLP) and then a pre-pro-B cell or B progenitor cell. The next steps include gene rearrangement to assemble the Ig molecule. Immunoglobulin heavy chains start with rearrangement of diversity and joining segments to form the pro-B cell. In the next step (pre-B cell), Ig heavy-chain recombination ( variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables, diversity, joining) is completed and the pre-B cell receptor is formed. Light-chain (kappa (κ) or lambda (λ)) rearrangement occurs, resulting in the expression of a complete IgM antibody molecule by an immature B cell. Formation of the mature B cell (naive) with both IgM and IgD follows.
Antigen-dependent stages take place in secondary lymphoid tissues. Once the mature B cell produces IgM and IgD, a class switch can take place to make IgE, IgG, and IgA. B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells are activated and become plasma cells or memory cells.

Image by Lecturio. License: CC BY-NC-SA 4.0

B Cells in the Immune System

Activated B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells

  • Differentiate into:
    • Plasma cells: 
      • Produce thousands of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins 
      • Migrate to the bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow
    • Memory cells:
      • React to antigenic stimulation (in response to reinfection)
      • Generate plasma cells which have high affinity antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins in secondary immune responses
  • Cell surface markers:
    • Ig
    • CD19, CD20, CD21 (important receptor for Epstein-Barr virus Epstein-Barr Virus Epstein-Barr virus (EBV) is a linear, double-stranded DNA virus belonging to the Herpesviridae family. This highly prevalent virus is mostly transmitted through contact with oropharyngeal secretions from an infected individual. The virus can infect epithelial cells and B lymphocytes, where it can undergo lytic replication or latency. Epstein-Barr Virus), CD40
    • B7

Immune responses

  • Primary immune response:
    • 1st encounter of the host with the antigen, with B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells activated and eventually plasma cells producing antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins
    • Antibodies are detected in the serum within 7 to 10 days.
      • IgM: 1st antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins to appear, then a decline is noted
      • Followed by other antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins ( e.g., IgG, IgA) as class switching takes place
    • Protection against invasive pathogens is slow and partially efficient.
  • Secondary immune response:
    • Follows activation of memory B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells
    • Faster and more effective in suppressing the infection progress 
    • Memory B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, having undergone affinity maturation in the primary response, produce abundant antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins with increased antigen-binding affinities 
    • IgM and IgG appear in less time, with IgG rising faster and in greater amounts than in the primary immune response.
The primary and secondary immune responses

Primary and secondary immune response:
In a primary immune response, naive B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells are stimulated by antigen. B cell activation and then differentiation into antibody-secreting cells occur. The antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins are specific for the eliciting antigen. The production of IgM is followed by IgG. While there is an immune response, the production is low-level. In the secondary immune response, the same antigen stimulates memory B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells, leading to the production of greater quantities of specific antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins that are produced in the primary response. The production and release of IgG also occur earlier.

Image by Lecturio.

Antibodies

Immunoglobulin (Ig)

  • Glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens
  • General components: 
    • 2 identical heavy and 2 identical light chains (referring to their molecular weight)
    • Disulfide bonds link the heavy chains to the light chains (forming a Y-shaped molecule)
    • Hinge region (confers flexibility)
    • Carbohydrate moieties (usually associated with the constant region)
  • The heavy chains (μ, δ, γ, α, or ε) are disulfide-linked to light chains (κ or λ).
  • Regions:
    • Variable region (antigen-binding)
      • The amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids sequence at the tips of the “Y,” which includes ends of both light and heavy chains
      • Has hypervariable region or complementarity-determining region (CDR) at each amino-terminal
      • The CDR provides antigen specificity, as it is complementary in structure to the antigenic determinant (epitope).
    • Constant region (effector functions)
      • Constitutes the remaining polypeptide
      • Binds Fc receptors and complement
  • Fragments (determined by location where the enzyme papain, splits the Ig):
    • Fab (fragment antigen-binding):
      • Contains the variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables regions and parts of the constant region of both heavy and light chains
      • Interacts with the antigen
    • Fc (fragment crystallizable):
      • The remaining part (tail) of the antibody (heavy chain only)
      • Constant region, Carbohydrate moieties
      • Complement binding
      • Confers Ig isotype (e.g., IgM, IgA)
  • The heavy chain makeup (constant region and Fc) determines the Ig class/isotype: 
    • μ: IgM
    • δ: IgD
    • γ: IgG
    • α: IgA
    • ε: IgE

Properties

  • Antibody diversity achieved by:
    • Multiple heavy and light chain segments
    • Rearrangements of the gene segments of the chains
    • Junctional diversity (addition or removal of nucleotides)
    • Combinatorial diversity (random combination of heavy and light chains)
    • Somatic hypermutation
  • Specificity achieved by:
    • Somatic hypermutation → affinity maturation ( variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables region)
    • Class switching (constant region)

Functions

Protection against infectious agents and their products by:

  • Neutralization of toxins and the infectivity of the pathogens: 
    • Utilizes the antibody’s Fab, which forms highly specific binding to the target
    • Binding prevents pathogen adherence.
  • Complement activation causing cell lysis and inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
  • Opsonization (with or without complement), promoting phagocytosis
  • Antibody-dependent cell-mediated cytotoxicity (ADCC): Immune cells are stimulated through Fc receptors, causing lysis of target cells.
  • Clearance of immune complexes:
    • Antigen/antibody complexes activate the complement system (antibody Fc regions in IgM and IgG bind C1q).
    • RBCs recognize these complexes, transporting them to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver and spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen for phagocytosis.

Clinical Relevance

  • X-linked agammaglobulinemia X-linked agammaglobulinemia X-linked agammaglobulinemia, also known as Bruton's agammaglobulinemia or Bruton's disease, is a rare, recessive genetic disorder characterized by the improper development of B cells, leading to a lack of mature B cells capable of responding to stimulation by cell-mediated immune responses or certain antigen-presenting cells. X-linked Agammaglobulinemia: results from mutations in the X chromosome gene encoding for Bruton tyrosine kinase (BTK), which is essential for B cell development and maturation. The disease is characterized by an absence of B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells leading to recurrent infections, primarily by encapsulated bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology: Overview and viruses, involving the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs, sinuses, and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin as well as the CNS. Treatment involves administration of immune globulin.
  • Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency (CVID): characterized by phenotypically normal B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells that cannot produce antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins. Common variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables immunodeficiency may be associated with several molecular defects that affect antibody production. The disease manifests in adults with recurrent sinopulmonary infections. The treatment is immune globulin replacement therapy.
  • Hyper-IgM syndrome Hyper-IgM syndrome The hyperimmunoglobulin M (hyper-IgM) syndrome, is a group of rare inherited immunodeficiency disorders characterized by low or absent serum levels of IgA, IgG, and IgE and normal or elevated levels of IgM. Hyper-IgM syndrome is most commonly caused by X-linked mutations in the CD40 ligand gene, which results in abnormal signaling between B and T lymphocytes. Hyper-IgM Syndrome: a heterogeneous group of conditions that can be of X-linked or autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritanceinheritance. The X-linked forms are characterized by defective helper T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells that cannot activate B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells to effect class-switch recombination. As a result, B cells B cells B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells produce only IgM, while other immunoglobulins Immunoglobulins Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, such as IgG, IgA, and IgE, are deficient. The patients present with neutropenia Neutropenia Neutrophils are an important component of the immune system and play a significant role in the eradication of infections. Low numbers of circulating neutrophils, referred to as neutropenia, predispose the body to recurrent infections or sepsis, though patients can also be asymptomatic. Neutropenia and recurrent sinopulmonary infections from childhood, and they are susceptible to Pneumocystis jiroveci Pneumocystis jiroveci Pneumocystis jiroveci is a yeast-like fungus causing pneumocystis pneumonia (PCP) in immunocompromised patients. Pneumocystis pneumonia is spread through airborne transmission and classically affects patients with AIDS, functioning as an AIDS-defining illness. Patients may present with insidious onset of fever, chills, dry cough, chest pain, and shortness of breath. Pneumocystis jiroveci/Pneumocystis Pneumonia (PCP) pneumonia Pneumonia Pneumonia or pulmonary inflammation is an acute or chronic inflammation of lung tissue. Causes include infection with bacteria, viruses, or fungi. In more rare cases, pneumonia can also be caused through toxic triggers through inhalation of toxic substances, immunological processes, or in the course of radiotherapy. Pneumonia and Cryptosporidium infections. Autosomal recessive forms are characterized by much higher IgM levels. There is a propensity for autoimmunity Autoimmunity Autoimmunity is a pathologic immune response toward self-antigens, resulting from a combination of factors: immunologic, genetic, and environmental. The immune system is equipped with self-tolerance, allowing immune cells such as T cells and B cells to recognize self-antigens and to not mount a reaction against them. Defects in this mechanism, along with environmental triggers (such as infections) and genetic susceptibility factors (most notable of which are the HLA genes) can lead to autoimmune diseases. Autoimmunity and development of B cell lymphomas. Hyper-IgM syndrome Hyper-IgM syndrome The hyperimmunoglobulin M (hyper-IgM) syndrome, is a group of rare inherited immunodeficiency disorders characterized by low or absent serum levels of IgA, IgG, and IgE and normal or elevated levels of IgM. Hyper-IgM syndrome is most commonly caused by X-linked mutations in the CD40 ligand gene, which results in abnormal signaling between B and T lymphocytes. Hyper-IgM Syndrome may also be secondary to congenital rubella Rubella Rubella (also known as German measles or three-day measles) is caused by a single-stranded, positive-sense RNA virus of the Togaviridae family. Rubella only infects humans and spreads prenatally via vertical transmission or postnatally via droplet contact. Congenital rubella is associated with a classic triad of symptoms: cataracts, cardiac defects, and deafness. Infection in children and adults may be mild and present with constitutional symptoms along with a viral exanthem. Rubella Virus syndrome and medications such as phenytoin. Treatment includes immune globulin replacement therapy and prophylactic antibiotics.
  • Hyper-IgD syndrome (HIDS): autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder associated with mutations in the gene coding mevalonate kinase, an enzyme participating in cholesterol synthesis. The disease manifests in childhood with recurrent episodes of chills and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, vomiting or diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, headache, and arthralgias. Physical signs include cervical lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, arthritis, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin lesions and orogenital aphthous ulcers. Serum levels of IgD are typically very high, although occasionally they may occasionally be within normal limits. Interleukin-1 receptor (IL-1R) antagonists, NSAIDs, and corticosteroids are used therapeutically. Febrile episodes tend to become less frequent in adulthood.

References

  1. Ballas, Z. (2021). Structure of immunoglobulins. UpToDate. Retrieved Aug 5, 2021, from https://www.uptodate.com/contents/structure-of-immunoglobulins
  2. Carroll, MC., & Isenman, DE. (2012). Regulation of humoral immunity by complement. Immunity, 37(2):199-207. https://pubmed.ncbi.nlm.nih.gov/22921118/
  3. Fernandez J. (2021). Hyper-IgM syndrome. MSD Manual. Merck & Co., Inc., Kenilworth, NJ, USA. Retrieved July 4, 2021, from https://www.merckmanuals.com/professional/immunology-allergic-disorders/immunodeficiency-disorders/hyper-igm-syndrome
  4. Kontzias, A. (2020). Hyper-IgD syndrome. MSD Manual. Merck & Co., Inc., Kenilworth, NJ, USA. Retrieved July 4, 2021, from https://www.merckmanuals.com/professional/pediatrics/hereditary-periodic-fever-syndromes/hyper-igd-syndrome
  5. Notarangelo, LD. (2021). Hyperimmunoglobulin M syndromes. UptoDate. Retrieved July 4, 2021, from https://www.uptodate.com/contents/hyperimmunoglobulin-m-syndromes
  6. Romberg, N. (2021). The adaptive humoral immune response. UptoDate. Retrieved July 4, 2021, from https://www.uptodate.com/contents/the-adaptive-humoral-immune-response
  7. Schroeder, HW, Jr, & Cavacini, L. (2010). Structure and function of immunoglobulins. J Allergy Clin Immunol, 125(2 Suppl 2):S41-52. https://pubmed.ncbi.nlm.nih.gov/20176268/

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