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. Antibodies undergo processes that improve antigen affinity and provide appropriate defense by class switching. 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. General functions include opsonization, neutralization of infectivity of the pathogens, cytotoxicity, and complement activation. Specific classes have unique defensive mechanisms.

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Overview

Immunoglobulins (Igs)

  • Glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens
  • General components: 
    • 2 identical heavy (H) and 2 identical light (L) chains (referring to their molecular weight):
      • Light chains: approximately 25 kDa each
      • Heavy chains: approximately 50 kDa each
    • Disulfide bonds link the heavy chains to the light chains (forming a Y-shaped molecule).
    • Hinge region (confers flexibility)
    • Carbohydrate moieties (associated with the constant region)
  • Different chromosomes encode the chains:
    • Heavy chains (μ, δ, γ, α, or ε): encoded by chromosome 14
    • Light chains  (κ or λ):
      • κ light chain: chromosome 2
      • λ light chain: chromosome 22

Ig regions and fragments

  • Both heavy and light chains in the Igs have variable and constant regions.
  • 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
  • The heavy chain and light chain regions are folded up into 3-dimensional segments called domains. 
    • The light chain has 1 variable domain and 1 constant domain.
    • The heavy chain has 1 variable domain but has different numbers of constant domains:
      • IgG, IgA, IgD: 3 constant domains
      • IgM and IgE: 4 constant domains
  • Fragments (determined by the 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
Immunoglobulin domains

Immunoglobulin domains:
The heavy chains and light chains are folded up into domain type structures. The light chain has 1 variable domain and 1 constant domain. The heavy chain has 1 variable domain but has different constant domains depending on the Ig molecule (IgG, IgA, and IgD have 3 constant domains, whereas IgM and IgE have 4 constant domains).

Image by Lecturio.

Immunoglobulin Genes

Ig gene segments

  • Heavy-chain genes (found within a single gene locus, IgH), are assembled from 4 gene segments:
    • Variable region (V)
    • Diversity segment (D)
    • Joining region (J)
    • Constant region (C)
  • The light chain genes (found as 2 separate gene loci—the κ locus (IgK) and the λ locus (IgL)) come from 3 gene segments:
    • Variable region (V)
    • Joining region (J) 
    • Constant region (C)

Gene rearrangements

  • In the B-cell stages of development, gene rearrangements proceed to assemble the Ig molecule. 
    • In the IgH chains, rearrangement starts with the D and J segments. 
    • IgH gene VDJ (variable-diversity-joining) recombination then occurs, forming a pre-B cell.
    • Light-chain VJ rearrangements follow.
  • From this process, a complete IgM antibody molecule is expressed and the mature B cell is formed. 
  • Gene rearrangements contribute to antibody diversity.

Class-switch recombination (CSR)

  • Also called class switching
  • Biologic mechanism by which B-cell production of Igs changes from one class to another.
    • IgM to other Igs → the constant region of the heavy chain (C) changes the μ (IgM) segment to γ (IgG), ε (IgE), or α (IgA). 
    • Switching is influenced by cytokines.
      • Tumor growth factor β (TGF-β): preferentially switches to IgA
      • IL-4: IgE
      • Interferon IFN-γ, IL-4: IgG
  • The constant region of the Ig heavy chain is changed, but the variable region remains unchanged.
  • Because the variable region is intact, specificity of the antibody does not change.

Processes of class-switch recombination

  • Excision of exons:
    • When antigens are encountered, mature IgM-positive B cells undergo CSR. 
    • Exons encoding the constant coding gene segment (Cμ) of the IgH are excised.
    • These exons are replaced with a new constant gene segment (e.g., Cγ, Cε, or Cα). 
    • Results in the B cell (originally expressing IgM) producing IgG, IgE, or IgA
  • DNA deletional-recombination reaction:
    •  Repetitive areas of DNA called switch regions are present:
      • Guiding DNA-modifying enzymes (activation-induced cytidine deaminase (AICDA) and uracil nucleoside glycosylase (UNG)) as to where to create DNA double-stranded breaks (DSBs)
      • Determining where the VDJ segment and the new constant region is joined by a repair enzyme
    • New Ig molecules are generated with a different constant region (but with the same affinity/specificity for the antigen given that the variable region is intact).
Class-switch recombination

Class-switch recombination (CSR):
The heavy chain has different gene segments: variable region (V), diversity segment (D), joining region (J) and constant region (C).
The heavy-chain C region determines the Ig class/isotype. When antigens are encountered, mature IgM-positive B cells undergo CSR. Exons encoding the constant coding gene segment (Cμ) of the IgH are excised. Repetitive areas of DNA called switch regions (black diamonds) are present.
The switch regions guide enzymes such as activation-induced cytidine deaminase (AICDA) as to where to create DNA double-stranded breaks (DSBs) and where the VDJ segment and the new constant region is joined by a repair enzyme. The Cμ is replaced with a new constant gene segment (e.g., Cγ, Cε, or Cα). In the image, Cγ1 is attached to the VDJ segment, creating IgG1.

Image: “Class switch recombination” by Ciar. License: Public Domain

Antibody Diversity and Specificity

Antibodies that are created have important properties (diversity and specificity) that are essential in the immune response.

Antibody diversity

Unique mechanisms creating antibody diversity include:

  • Having multiple V, D, and J segments: 
    • As already mentioned, in early B-cell development, the heavy chains and light chains have multiple segments:
      • V, D, J, and C for heavy chain
      • V, J, and C for light chain
  • Rearrangements of the V, D, and J segments:
    • DNA sequences (called recombination signal sequence (RSS)) flank each gene segment.
    • These sequences are recognition sites for the joining process.
    • Recombinase enzyme complexes RAG1 and RAG2 (recombination activating genes 1 and 2) recognize the RSS and catalyzes the joining process.
    • Deficiency in RAG1 or RAG2 can produce nonfunctional B cells. 
    • After the heavy-chain segments, the light-chain segments are also recombined.
  • Junctional diversity:
    • Joining of antibody gene segments can be imprecise.
    • A number of nucleotides can be removed and/or can be inserted from the ends of the recombining gene segments.
  • Combinatorial diversity:
    • Diversity is created by the random pairing of the heavy and light chains.
  • Somatic hypermutation: 
    • Point mutations occur with repeated antigen stimulation (from primary to secondary responses).
    • Increases affinity to antigen
    • Creates additional diversity to the antibody

Specificity

  • Somatic hypermutation leads to affinity maturation (in the variable region), creating an enhanced ability to recognize and bind antigen.
  • Class switching (which affects the constant region) also contributes to antibody specificity.
B-cell activation and maturation processes in the germinal center

B-cell activation and maturation processes taking place in the germinal center:
On activation, the B cell moves from the mantle zone and enters the germinal center. B-cell proliferation (clonal expansion) takes place, and antibody affinity to the antigen is enhanced through the process of somatic hypermutation. Repeated cycles of proliferation and hypermutation fine-tune the B-cell receptor. However, not all B cells continue to differentiate, especially if affinity is weak. Apoptosis follows if the antigen–antibody binding is not optimized. B cells with strong affinity survive (selection), with the help of survival signals from follicular dendritic cells and T cells. These selected B cells move on to class switching and differentiation into plasma cells or memory cells.

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

Classes and Characteristics

Classes

  • IgG:
    • Major class of Ig in the serum and extravascular spaces
    • Subclasses: IgG1 (65% of IgG), IgG2, IgG3, IgG4
    • Crosses the placenta, thus, the most abundant Ig in newborns
  • IgM:
    • 1st antibody in response to an antigen
    • The pentameric structure of IgM has 10 binding sites, making it the Ig with the highest binding capacity.
    • Does not cross the placenta
  • IgA:
    • Major Ig for mucosal immunity (found in secretions of the respiratory, GI, and genitourinary tracts)
    • About 10%–15% of total Igs in the serum
    • Subclasses: IgA1, IgA2
  • IgE:
    • Lowest quantity in the serum
    • Fc region binds to its receptors in basophils, eosinophils, and mast cells.
  • IgD:
    • Low amounts in the serum
    • Major surface Ig in mature naive B cells

Monomers and polymers

  • The antibody unit is a small molecule (a monomer).
  • IgA and IgM form antibody polymers (formed from chemically bonded monomers).
    • IgA:
      • A monomer resembling IgG in the serum
      • In mucus, secreted IgA forms dimers, 2 monomers with the J chain (stabilizing molecule), and a secretory component.
    • IgM:
      • Secreted polymers of 5 antibodies (pentamer) bound together by J chain
      • Has 10 identical antigen-binding sites
      • Structure contributes to antibody efficiency, complement fixation, and other antibody–antigen interactions

Antigen–antibody interaction

  • The area of the antigen recognized by the antibody is called the epitope.
    • A single antigen may have several epitopes. 
    • Each epitope can be bound by a different antibody.
  • Antibody binds to antigen noncovalently (reversible):
    • Hydrogen bonds
    • Electrostatic interactions
    • Van der Waals interactions
    • Hydrophobic interactions
  • Affinity is the strength of the bond formed between the antibody’s antigen-binding site and the antigen epitope (between 2 molecules).
  • Avidity is the overall or combined strength of antibody–antigen interactions (as the antigen can have multiple epitopes) and is dependent on the:
    • Number of antibody antigen-binding sites in antibody (antibody valency)
    • Affinity of the binding sites for antigen
    • Structural arrangement of interacting parts of antibody–antigen

Functions

General functions

  • Neutralization of toxins and the infectivity of pathogens: 
    • Bacterial toxins are neutralized and effects are inactivated.
    • Neutralizing antibodies use the Fab (which forms highly specific binding to the target attachment sites or receptors) → prevents pathogen adherence 
    • Some Igs cause organisms to aggregate (IgA → agglutination → entrapment in mucus)
    • After attachment, fusion with host membranes can be inhibited.
  • Complement activation and generation of membrane attack complex (MAC) causing cell lysis and inflammation
    • Antibodies (primarily IgM and IgG) activate the complement system.
    • MAC: 
      • Activated complement components are C5b, C6, C7, C8, and C9.
      • Introduces large pores on the pathogen surface, leading to pathogen death
  • Opsonization (with or without complement) for phagocytosis
    • Involves coating of pathogens by molecules that enhance phagocytosis
    • Antibodies, especially IgG, can function as opsonins (like C3b).
  • Antibody-dependent cellular cytotoxicity (ADCC):
    • Involves Fc-bearing immune cells (e.g., natural killer cells) able to produce toxic molecules
    • These cells are stimulated through Fc receptors by Igs (particularly IgG). 
    • Activation of the immune cell releases toxic molecules, causing lysis of target cell.
    • IgE also triggers ADCC:
      • The eosinophil (with the Fc receptor) recognizes IgE.
      • Helminth-bound IgE stimulates eosinophil degranulation, and the cytotoxic granules kill parasites that are too large to be phagocytosed.
  • Clearance of immune complexes:
    • Antigen–antibody complexes activate the complement system: 
      • Antibody Fc regions in IgM and IgG bind C1q.
      • Immune complexes are opsonized with C3b fragments.
    • Immune complexes, bearing C3b fragments, bind to complement receptor 1 (CR1) on RBCs. 
    • RBCs then take the immune complexes to the liver and spleen, where macrophages phagocytose the complexes.

Functions of the different Ig classes

  • IgG:
    • Main antibody in secondary immune response
    • Functions are affected by subclass, but, in general, IgG:
      • Fixes complement
      • Participates in ADCC (binding Fc receptors)
      • Enhances phagocytosis (opsonin)
    • Ability to cross the placenta, mediated by receptors on placental cells for IgG Fc.
      • IgG antibodies produced in the mother against pathogens she encounters are passed to the fetus.
      • Maternal IgG wanes 6–12 months after birth.
  • IgM
    • Monomer form serves as a B-cell receptor (BCR) in naive B cells.
    • Facilitates activation of the B cells by binding to helper T cells
    • Produced in the primary immune response
    • Fixes complement, leading to lysis of microorganisms
    • Agglutinin: can agglutinate pathogens, thus facilitating pathogen elimination
  • IgA: 
    • A secretory component is added, allowing transport of IgA across the mucosa.
    • The secretory form (dimer) prevents bacterial colonization of mucosal surfaces.
    • Major Ig in secretions: tears, saliva, colostrum, mucus
  • IgE: 
    • Binding of allergen to IgE triggers release of inflammatory mediators from mast cells and basophils (allergic response)
    • Important in elimination of parasites (eosinophils bind to IgE-coated helminths, leading to killing of the parasite) 
  • IgD:
    • Together with IgM, constitutes the BCR of naive B cells

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 the absence of B cells, leading to recurrent infections, primarily by encapsulated bacteria and viruses and involving the lungs, sinuses, and skin as well as the CNS. Treatment involves administration of immune globulin.
  • Common variable immunodeficiency (CVID): also known as humoral immunodeficiency. Common variable immunodeficiency is a disorder of the immune system characterized by reduced serum levels of IgG, IgA, and IgM.  The underlying causes of CVID are largely unknown. Individuals with this condition are prone to infections in the GI and the upper and lower respiratory tracts. CVID is also associated with a higher risk of developing autoimmune disorders, granulomatous diseases, and malignancy. The treatment is immune globulin replacement therapy.
  • Hyper-IgM syndrome: characterized by normal or elevated levels of IgM with decreased or absent levels of other Igs. There are X-linked and autosomal recessive types of hyper-IgM syndrome. The syndrome presents with recurrent sinopulmonary infections, chronic diarrhea, and lymphoid hyperplasia. The diagnosis is verified by genetic testing. Treatment includes Ig replacement therapy and prophylactic antibiotics. Hematopoietic stem cell transplantation is another option. 
  • IgA deficiency: characterized by low levels of IgA with normal IgG and IgM levels. IgA deficiency is the most common primary immunodeficiency. Many individuals are asymptomatic; however, there is a potential for recurrent infections as well as autoimmune disease. Individuals may be prone to anaphylactic transfusion reactions because of the presence of IgA in blood products. Some of these cases eventually progress to CVID. The treatment involves prophylactic antibiotics and avoidance of blood products that contain IgA.

References

  1. Forthal, D.N. (2014) Functions of antibodies. Microbiology Spectrum 2(4):1–17. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159104
  2. Matthews, A.J., Zheng, S., DiMenna, L.J., Chaudhuri, J. (2014). Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair. Advances in Immunology 122:1–57. https://doi.org/10.1016/B978-0-12-800267-4.00001-8
  3. Riedel, S., Hobden, J.A., Miller, S., Morse, S.A., Mietzner, T.A., Detrick, B., Mitchell, T.G., Sakanari, J.A., Hotez, P., Mejia, R. (Eds.). (2019). Immunology. Chapter 8 of Jawetz, Melnick, & Adelberg’s Medical Microbiology, 28th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2629&sectionid=217769996
  4. Schroeder, H.W., Jr., Cavacini, L. (2010). Structure and function of immunoglobulins. Journal of Allergy and Clinical Immunology 125(2 Suppl 2):S41–S52. https://doi.org/10.1016/j.jaci.2009.09.046

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