Molecular basis of immunoglobulin diversity of primary and secondary antibody response, somatic recombination, isotype skipping.

Antibodies are an important line of defense against pathogen that invade our bodies. However, their function is reliant on their ability to recognize the antigen and their ability to bind to an antibody facilitates an immune cascade that leads to neutralization of the threat to our body

Molecular basis of immunoglobulin diversity of primary and secondary antibody response

Antibodies most often known for the role and immune cascade they initiate after being triggered by the presence of antigen. Antibody diversity is birthed through the process somatic recombination.

Antibody response is a reaction of B cells that causes a difference in the constitution of human sera due to elevation of Immunoglobulins. From current theories, The reactions of the human body to foreign particles or pathogens may be classified into primary and secondary antibody response.

Primary response

The primary response is characterized by the following features:

• Immediately after exposure to antigen, there are no antigen specific antibodies and there would be period of lag between the presence of antibodies and exposure, some speculate around 5 - 10 days
• During which B cells bind to the antigen which would dependent on the stimulation of T helper cells
• These B cells divide and differentiate then produce antibodies like IgG and IgM.
  • IgM production precedes they are distinctly recognized for their role in complement activation
  • IgG is specifically praised for the role in plays in opsonization (the use of opsonins to bind and highlight foreign pathogens to cells like phagocytes that remove them)
    • It may also activate complement system.
• Post infection, the levels of Immunoglobulins drop to neat negligible levels but never zero because of the persistence of "long lived plasma cells" that retain the ability to produce antibodies specific to the particular antigen.
  • This plays a role in the length of duration prior to the onset of the secondary antibody response

Secondary response

The key feature that separates a secondary infection from a primary infection is the speed of the response formed by the immune system. This is reliant on the presence of memory cells.

Key characteristics for a secondary immune response:

• The response is primarily reliant on the presence of memory cells which plays a significant role in the reduced duration of the lag phase.
• Which could result in an overlap between the lag and exponential phase
• The peak in the curve related to antibody production would be significantly higher than the response.
• Class switched antibodies are more often associated with this type of response.
• This type of response can be generated over long period of time due to the persistence of memory cells

Somatic recombination

During the primary antibody response, the aforementioned diversity is relied on for recognition. A pre immune antibody repertoire is important part of the defense our body builds against pathogens.

• Pre immune antibody repertoire refers to the antibodies that are produced by the human body in the absence of stimulation by an antigen.
  • This process is driven by somatic recombination
  • This produces a cohort of antibodies that can provide defense against a wide array of antigens belonging to pathogens including foreign material

This wide spectrum of the antigen recognition arises because during development of lymphocytes, the genes that code for variable region specific VDJ segments undergo recombination. The recombination process starts with double strand breaks produced by recombination activating genes (RAG 1 and RAG 2). The process of recombination is mediated by the VDJ recombinase which consists RAG1 and RAG2 proteins which perform the DNA cleavage. The double strand breaks are then rejoined using the method of Non homologous end joining which occurs in all cell cycles stages. The generation of antibody diversity in somatic recombination is two fold process; at first the difference is reliant on the rearrangement of VDJ but also on the joining mechanism which can be characterized by the loss or the addition of the extra nucleotides.

The process itself occurs in the primary lymphoid organ (bone marrow and thymus). The first recombination event to occurs in the heavy chain locus between D and J gene segments. Followed by the joining of one V gene segment. The primary RNA then undergoes the process of addition of the polyadenylated tail and remove the sequence between VDJ and the constant gene segment. Similar events occurs for the light chain. But the events in light chains and heavy chains differ because the light chain segments lack a D segment so the recombination is usually followed by the VJ segment addition to the constant chain gene during primary transcription.

Isotope switching

This the process the brings about different isotope of immunoglobulins against a specific antigen. Human body produces five different isotopes of antibodies determined by constant region of the heavy chains. This can be emphasized by the fact that naive B cells express IgM predominantly. Due to lack of changes that occur in the variable region, the antigen specificity of the antibodies don't differ between the classes. Thus the production of different isotopes is seen to produced from the daughter cells of the same activated B cells. B cells can only produce one isotope at a time.

The process involves the deletion of segment in the constant region followed by the rejoining the remaining segments which leads to the diversity. The double strand break required for this process occurs at site called the switch regions. These regions are found upstream from the constant regions. The enzymes involved are called Activation induced deaminase, uracil DNA glycosylase and apyrmidic/apurinic acid endonculeases which creates the nick at two separate S regions. Similar to somatic recombination, the remaining after deletion of the regions in between S regions, rejoining by a process of Non homologous end joining follows which connects variable domain exon with constant domain exon.