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). Humoral immunity is the 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 play a major role, producing antibodies or immunoglobulins. Arising from the bone marrow, 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 go through processes enhancing antigen affinity, class switching, and differentiation to plasma cells and memory cells. Plasma cells produce the antibodies, while memory 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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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
    • Humoral immunity: adaptive response in the fluids (humors) involving B cells and immunoglobulins

Innate vs. adaptive immunity

Table: Innate versus adaptive immunity
Innate immunityAdaptive immunity
GeneticsGermline encodedGene rearrangements involved in lymphocyte development
Immune responseNonspecificHighly specific
Timing of responseImmediate (minutes to hours)Develops over a longer period of time
Memory responseWithout memory responseWith memory response, which responds quickly upon recognition of antigen
Recognition of pathogenPattern recognition receptors (PRRs) such as TLRs recognize pathogen-associated molecular patterns (PAMPs).
  • Memory cells (T and B cells)
  • Activated B cells
Components
  • Chemical and biological barriers (e.g., gastric acid, vaginal flora)
  • Anatomical barriers (e.g., skin)
  • Cells (e.g., granulocytes)
  • Secreted proteins:
    • Enzymes (e.g., lysozyme)
    • Other PRRs (e.g., antimicrobial peptides (AMPs))
    • Cytokines*
    • Complement* system
  • Cell-mediated immunity: T cells
  • Humoral immunity: B cells, 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 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 (T helper cells, cytotoxic T cells) and secreted proteins (antibodies produced by B cells)
  • Functionality takes days, but once engaged, repeat encounters with the offending agent elicits a faster response.
  • The components, B and 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
    • CD4+ T (helper) cells: Different subsets perform multiple functions (including cytokine production, activation of macrophages).
    • CD8+ T (cytotoxic) cells: defend against intracellular bacteria and viruses via destruction of infected cells. 
    • Memory T cells: respond to antigen reexposure
  • Other components:
    • 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 present antigens to the T cells.

Humoral adaptive immunity

  • Antibody-mediated immunity
  • B cells:
    • Differentiate into plasma cells, producing antibodies (through the help of T cells)
    • Differentiate into memory cells, briskly responding to reinfection
    • Act as antigen-presenting cells to T cells (expressing MHC II)
  • Antibodies, along with complement, help the cells of the innate system against extracellular, encapsulated bacteria.
  • Antibodies can neutralize toxins, such as tetanus toxin, and viruses.

Development of B Cells

B cells

  • Arise from the common lymphoid progenitor 
  • In stages, B cells develop in the 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, 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 region (where the antigen binds)
  • Gene rearrangements (uniting different gene segments) within B cells are needed to assemble the Ig molecule.
  • This process also produces a repertoire of diverse 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 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.
    • Some antigens, like the polysaccharides of a bacterial cell (e.g., Streptococcus pneumoniae and Haemophilus influenzae), can directly stimulate 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 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, 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 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

  • Differentiate into:
    • Plasma cells: 
      • Produce thousands of antibodies 
      • Migrate to the bone marrow
    • Memory cells:
      • React to antigenic stimulation (in response to reinfection)
      • Generate plasma cells which have high affinity antibodies in secondary immune responses
  • Cell surface markers:
    • Ig
    • CD19, CD20, CD21 (important receptor for Epstein-Barr virus), CD40
    • B7

Immune responses

  • Primary immune response:
    • 1st encounter of the host with the antigen, with B cells activated and eventually plasma cells producing antibodies
    • Antibodies are detected in the serum within 7 to 10 days.
      • IgM: 1st antibodies to appear, then a decline is noted
      • Followed by other antibodies ( 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
    • Faster and more effective in suppressing the infection progress 
    • Memory B cells, having undergone affinity maturation in the primary response, produce abundant antibodies 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 are stimulated by antigen. B cell activation and then differentiation into antibody-secreting cells occur. The antibodies 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, leading to the production of greater quantities of specific antibodies 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 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 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 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
  • 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 and spleen for phagocytosis.

Clinical Relevance

  • 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 leading to recurrent infections, primarily by encapsulated bacteria and viruses, involving the lungs, sinuses, and skin as well as the CNS. Treatment involves administration of immune globulin.
  • Common variable immunodeficiency (CVID): characterized by phenotypically normal B cells that cannot produce antibodies. Common variable 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: a heterogeneous group of conditions that can be of X-linked or autosomal recessive inheritance. The X-linked forms are characterized by defective helper T cells that cannot activate B cells to effect class-switch recombination. As a result, B cells produce only IgM, while other immunoglobulins, such as IgG, IgA, and IgE, are deficient. The patients present with neutropenia and recurrent sinopulmonary infections from childhood, and they are susceptible to Pneumocystis jiroveci pneumonia and Cryptosporidium infections. Autosomal recessive forms are characterized by much higher IgM levels. There is a propensity for autoimmunity and development of B cell lymphomas. Hyper-IgM syndrome may also be secondary to congenital rubella syndrome and medications such as phenytoin. Treatment includes immune globulin replacement therapy and prophylactic antibiotics.
  • Hyper-IgD syndrome (HIDS): autosomal recessive disorder 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, abdominal pain, vomiting or diarrhea, headache, and arthralgias. Physical signs include cervical lymphadenopathy, splenomegaly, arthritis, 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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