Affinity maturation

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The affinity maturation (English affinity maturation is) a process of the immune system of mammals , whose task to improve the efficiency of the immune response after repeated contact with an antigen is. Affinity maturation takes place in mature B lymphocytes in the germinal centers of the lymph nodes and is based on an increased mutation rate in these cells, also known as somatic hypermutation , and a clonal selection . It takes place long after V (D) J recombination , which is responsible for the innate diversity of B lymphocytes. The natural process of affinity maturation is also mimicked under artificial conditions in the enhancement of recombinant antibodies and antibody fragments and is therefore referred to as in vitro affinity maturation .

physiology

After the first contact of suitable IgM -bearing B lymphocytes with a presented antigen , the majority of these cells differentiate into short-lived plasma cells , which are responsible for the production of antibodies. Another part migrates to the germinal centers of the lymph nodes, where random mutations affecting the variable domains of the light and heavy chains of immunoglobulins occur. The mutation rate is increased by up to 1,000,000 times compared to other body cells and leads to an average of one mutation within the variable domains per cell generation. Activation Induced Cytidine Deaminase (AID) plays an important role in this form of somatic hypermutation . It is essential for the survival of the mutated B lymphocytes that they interact with the antigen presented by follicular dendritic cells and follicular T helper cells via their membrane-bound antibodies . They not only compete with each other, but also with the IgG antibodies formed as a result of the primary response of plasma cells. Due to the competitive pressure, only those B lymphocytes survive whose presented antibodies have an improved affinity for the antigen. Of the large number of mutants formed, only very few clones ultimately survive . After this selection, the surviving B-lymphocytes differentiate into memory cells and long-lived plasmablasts while retaining the genetic information of the mutated and selected antibodies. The plasmablasts migrate to the bone marrow, where they differentiate into antibody-segregating plasma cells by alternative mRNA splicing. The repression of the transcription factor Bcl-6 inhibits p53, so that strong proliferation can take place despite hypermutation. The memory cells circulate in the blood and lymph organs. Upon renewed contact with the relevant antigen, they can be activated immediately in order to provide these optimized antibodies in a short time.

Biotechnological use

Based on the model of in vivo affinity maturation, in vitro affinity maturation is used in biotechnology to increase the affinity of antibodies and antibody fragments under laboratory conditions. Like her role model, she uses mutation and selection to increase efficiency. The in vitro -Affinitätsreifung applies in particular to antibodies and fragments derived therefrom, application no affinity maturation in vivo subject. These include in particular those that were found by screening synthetic or naive antibody libraries. In addition, the principle of in vitro affinity maturation can also be extended to other biomolecules, such as antibody mimics .

For the in vitro -Affinitätsreifung display techniques, such as phage display used. They offer the advantage that a protein expressed on the surface is indirectly linked to the coding DNA . The coding DNA can be changed with the help of chain shuffling or with the help of mutagenesis techniques such as the use of E. coli mutator strains, β-radiation , chemical mutagens or error-prone PCR . Using display techniques for selection, antibody fragments with an affinity in the low nanomolar range can be achieved after two to three mutation and selection cycles.

Individual evidence

  1. ↑ Michael McHeyzer-Williams: Fundamental immunology . Ed .: William E. Paul. Lippincott Williams & Wilkins, 2008, ISBN 978-0-7817-6519-0 , B Lymphocyte Biology, pp. 289-312 .
  2. ^ Grace Teng, F. Nina Papavasiliou: Immunoglobulin Somatic Hypermutation. In: Annual Review of Genetics. 41. Palo Alto 2007, ISSN  0066-4197 , pp. 107-120, doi : 10.1146 / annurev.genet.41.110306.130340 .
  3. ↑ Andre Frenzel, Lorin Roskos, Scott Klakamp, ​​Meina Liang, Rosalin Arends, Larry Green: Antibody Affinity . In: Stefan Dübel, Janice M. Reichert (Eds.): Handbook of Therapeutic Antibodies . tape II. . Wiley-VCH-Verlag, Weinheim 2007, ISBN 978-3-527-31453-9 , pp. 145-169 , doi : 10.1002 / 9783527682423.ch6 .