Immunoglobulins are molecules providing immunity and protection from infections and microbial attacks. They have a typical Y shape. That is the reason they catch hold of microbes such as bacteria and viruses.
The unique molecule of the microbes is known as an antigen. The antibody's Y structure has a region known as a paratope. It binds with the epitope of the antigen. Then it makes the process of elimination easier. Antibodies have a variety of functions. It is important to judge the greatness of an antibody based on its biological effect on a pathogen or the toxins produced by a pathogen. It is an important hallmark for many lab tests that an antibody binds to a particular antigen. Studying and knowing about antibodies is key to developing potential vaccines and therapeutics. Functions of the antibodies, such as virus neutralization, may help to inhibit pathogenesis.
The inhibitory results of antibodies on pathogenic organisms were recorded since the 1800s. Since then, many things have been known concerning the means that underlie the anti-microbial action of antibodies. However, these Y-shaped molecules often have numerous functions in vitro and in vivo. They either involve direct means or via interactions with FcRs or compliments.
Modern means, such as knockout mice or antibodies engineered to repeal or improve functions have demonstrated promising results for more accurate investigations of antibody function. Yet, major questions about how an antibody plays roles in vivo remain unanswered, and multiple actions are possible to contribute to the anti-microbial influence.
The complexity of our immune system mainly depends on the immune cells such as the B cells, T cells, various antibodies, and other cells. As soon as a foreign molecule or a microbe enters the body, our immune system gets activated. The soldiers of the immune system, mainly the immune cells and the antibodies come forward and activate a cascade of mechanisms involved in killing the foreign particles and the microbes. They not only eliminate the microbe from the body but also remember it as an enemy so that when the same microbe re-enters next time, they easily eliminate it. The antibodies usually denoted as Y-shaped molecules, bind to the antigens and help in eliminating them. The antibodies exhibit diverse nature and their synthesis completely depends on certain gene expressions. These antibodies show receptors specific to the antigens. Although there are few genes in the human body, the antibodies have very diverse receptors. Hence, they identify many different types of antigens.
While distinguishing or recognizing foreign substances, our immune cells do not get confused with the cells inside the body. Hence, they differentiate the foreign cells and their own cells cleverly. The phenomenon of identifying a foreign antigen is known as immune recognition. Antibody structures exhibit complexity. Thus, they recognize a wide array of foreign antigens. Sequencing data reveals a specific amino acid sequence in the variable region and a few invariant sequences in the constant regions. Determination of an antibody involves specificity and sensitivity. The property of the antibody of being specific helps to determine the homologous and heterologous epitopes. The sensitive property of an antibody helps to recognize the antigen in between thousands of other substances. It is important to study the antibody structure before studying the diversity.
Image 1: Antibody diversity
Antibodies are Y-shaped glycoproteins with four main polypeptide chains. The two long polypeptide chains with many amino acids are known as heavy chains. The remaining two chains consisting of short polypeptides are known as light chains. Each light chain gets connected to a heavy chain through a disulfide bond. The heavy and the light chains mainly consist of two distinct regions. The tips of heavy and light chains consist of the variable region (V). The remaining is known as a constant region (C). The variable region attaches to the antigen. A normal human being consists of one million antibodies with different antigen-binding specificities. Hence, the variable region consists of different amino acid sequences. Five types of heavy chains include γ, α, ε, δ, and μ. Two types of light chains are known as κ and λ. Types of antibodies in humans include IgA, IgD, IgE, IgG, and IgM respectively.
Antibody diversity and Genetics:
A separate set of multigene families encode for heavy and light chains situated on different chromosomes. The light chain genes are present on the 2nd and 22nd chromosomes. The heavy chain genes are present on the 14th chromosome. Several coding sequences known as gene segments get separated by the non-coding segments. On maturation of the B-cells, these genes get rearranged, thereby forming a functional immunoglobulin. Restriction mapping is a kind of physical mapping that shows specific sites for the restriction enzymes. They involve separation by lengths and are marked in numbers by bases. Hence, the study of DNA segments encoding the antibodies involves a restriction map.
The DNA segments encoding a variable region get separated from the DNA segment encoding a constant region by an intermediate region encoding a joining segment. The heavy chain studies revealed the presence of one more region known as the D region (for diversity) placed between the V and J regions. A non-coding region separates each of the coding regions. A single type of gene gets expressed for each V, D, J, and C region in a single antibody molecule. Various DNA coding regions naturally recombine to produce a diverse antibody.
Image 2: Antibody structure
Various regions
|
Total Genes
|
The number of genes expressed
|
Variable region (V)
|
86
|
1
|
Diversity region (D)
|
30
|
1
|
Joining region (J)
|
9
|
1
|
Constant region (C)
|
11
|
1
|
Table: The expression of the genes in various regions
Splicing and recombination:
Naturally, DNA recombination occurs in the coding segments. For forming a heavy chain, splicing of any one variable region on a D region occurs followed by a J region. This process of splicing is known as V-D-J joining. Then the constant portion of the heavy chain undergoes splicing. The transcription and translation processes follow these events. RNA processing involves the splicing of the introns or the non-coding regions. When the antigen stimulates an immune response, the heavy chain DNA undergoes a further rearrangement in which V, D, and J combine with any C gene segment. The V, D, J, and C regions for a heavy chain DNA are known as VH, DH, JH, and CH respectively. The process is known as class switching. Exactly how the process occurs remains unclear. However, there are flanking regions situated upstream of the CH region consisting of multiple copies of short repeats (GAGTC and TGGGG). Mutations also help to increase the genetic variation of the antibodies.
Image 3: V-D-J rearrangement
Antibody diversity differs in various species:
The creation of most of the immunoglobulin genes is similar in humans and mice. There is a combinatorial repertoire of immunoglobulin genes. The combinatorial rearrangements of VDJ gene segments are germ-line based. It occurs primarily in the bone marrow. In organisms such as birds, rabbits, sheep, cattle, and others, the primary repertoire gets generated in the gut-associated lymphoid tissue (GALT). Many species do not undergo combinatorial VDJ rearrangements. Chickens involve a limited repertoire of functional VDJ genes. Hence, the B cells migrate to the Bursa of Fabricius and undergo rapid proliferation and diversification mediated by gene conversion. In rabbits, gene conversion and somatic hypermutation occur in the GALT in the specialized microenvironments of the appendix. The sheep and the cattle diversify their antibodies in the Peyer’s patch. The jawed vertebrates including the cartilaginous fish undergo VDJ rearrangements. Jawless fish such as Hagfish and Lampreys lack adaptive immunity. These fish use completely different genes known as variable lymphocyte receptors (VLRs) to generate an immune response. These VLRs are leucine-rich repeats capable of producing somatic diversity. Not only animals and fish but also plants and insects possess immunoglobulin genes.
Gene conversion is not an ordinary process. It extensively diversifies the rearranged genes. Gene conversion is a special case of somatic mutation, thereby known as somatic hypermutation. The word somatic hypermutation indicates the occurrence of a high-class mutation in the variable regions of the immunoglobulin genes. Thus the gene sequence portions get modified assuming the corresponding sequence of the donor gene. The donor gene acts as a template gene. This type of somatic mutation is known as templated somatic mutation. Once the antigen enters the immune system, it gets exposed to millions of antibodies. But only a few types of antibodies have a sufficient affinity to trigger an immune response. Depending on the affinity binding, antibodies with sufficient affinity interact with the antigen.
AgDscam genes in mosquitoes:
Insects such as mosquitoes possess genes encoding immunoglobulins. However, they lack specific mechanisms such as somatic hypermutation and recombination. Hence, mosquitoes have a different mechanism. The researchers at John Hopkins discovered AgDscam, a way in which mosquitoes combine their immunoglobulin domains of a single gene. AgDscam indicates Anopheles gambiae Down’s syndrome cell adhesion molecule. It produces a variety of pathogen-binding proteins. It follows the process of alternative splicing guided by immune signal transduction pathways. Hence, it helps to increase the binding capacity of various pathogen binders.
Thus, in conclusion, antibody diversity occurs through gene recombination. The process of gene recombination varies from organism to organism. Humans involve enzyme-mediated VDJ recombination, gene conversion, and somatic hypermutation. The other organisms may involve slightly different mechanisms. Hence, these genes play an important role in building the immune system.
References:
References:
[1] Kuby Immunology
[2] Immunology, Pathak, and Palan
[3] Genetics, 9th Edition (Multicolour Edition), Verma P.S. & Agarwal V.K.
[4] Principles of genetics, 8th ed, Gardner, M. J. Simmons, D. P. Snustad
[5] Insect Infection and Immunity: Evolution, Ecology, and Mechanisms, Jens Rolff, Stuart Reynolds
[5] Insect Infection and Immunity: Evolution, Ecology, and Mechanisms, Jens Rolff, Stuart Reynolds
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