Tx Immunology - Professor Richard Kirk 2023

Professor Richard Kirk
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Plasma Cells and Antibodies
Plasma Cells
Plasma cells are derived from activated B cells and, like lymphocytes undergo differentiation. They mature into one of two types. Short lived (plasmablasts) lasting only a few days, mainly reside in secondary lymphoid organs (lymph nodes, the spleen, the tonsils and certain tissue in various mucous membrane layers in the body) and mainly produce low affinity antibodies e.g. IgM. They all (mostly) retain the CD+19 marker and early development stages of plasmabasts variably express CD20. In contrast, long lived plasma cells, otherwise known as memory plasma cells, do not express CD20.  They are known to survive for years, sometimes decades and produce high affinity antibodies e.g. IgG. Their longevity is enabled by residing in the bone marrow (a relatively protected site).
Plasma cell function is to produce immunoglobulin and this they do in extra-ordinary numbers (103 molecules per second). The half life of an antibody is 21 days. Plasma cells may continue to produce antibodies indefinitely in the presence of ongoing stimulation (e.g. the presence of a homograft) or cease until re-stimulated e.g. re-infection or, in the transplant context, rejection causing upregulation of donor HLA expression.  However they may also continue to produce antibody without any ongoing stimulation as is the case following smallpox vaccination where serum antibodies have been shown to be maintained in humans 70 years later, despite smallpox being eradicated.

Rejection is an inflammatory response and it is known that inflammation increases plasma cell antibody production which may cease once the inflammation resolves. This, along with the variable expression of surface HLA, may explain the appearance of donor specific antibodies early post transplant when the graft is recovering from ischemia-reperfusion injury or at the time of rejection which subsequently disappear.

Clearly much remains to be understood about plasma cell regulation.
Antibody Classes
Mature B cells express IgM & IgD as their BCR. When activated to become plasmablasts they initially secrete IgM. They then undergo class switching to secrete IgG, IgA or IgE isotypes. IgG is by far the most common class accounting for more than 75% of all immunoglobulins in the blood and the most important in transplant. IgG is divided into 4 subclasses IgG1-4. The subclasses have different properties  and respond to different stimuli. For example IgG1 & IgG3 bind most strongly to C1q and thus initiate the complement cascade.
Antibody Function

Antibodies perform several functions (Figure 1). Antibodies can simply block interactions of  molecules or they can trigger the complement dependent cytotoxicity (CDC) pathway which "punches" a hole in the cell membrane leading to its demise. Acting more slowly they can bind to cell wall antigens and then link to cells of the adaptive immune system (antibody dependent cellular cytotoxicity - ADCC) which cause cell death through cytotoxic T cells or by binding with the toll like receptor (TLR) of an innate cell enhancing its ability to destroy the organism or attract a NK cell with the same effect.
Figure 1. https://absoluteantibody.com/antibody-resources/
Further Reading
  • Mechanisms of central tolerance for B cell. D Namazee. Nature Reviews Immunology 2017;17:281
  • https://absoluteantibody.com/antibody-resources/
  • Memory B Cells and Long-lived Plasma Cells. Ionescu and Urschel. Transplantation 2019;103: 890–898
  • Advances in Plasma Cells in Health and Diseas. Lee, F. E.-H., Wrammert, J., Cenci, S., eds. (2020). e. Lausanne: Frontiers Media SA.doi: 10.3389/978-2-88966-266-1
  • Antibody Structure and Function: The Basis for Engineering Therapeutics. Chiu et al. Antibodies 2019, 8(4), 55; https://doi.org/10.3390/antib8040055
  • IgG subclasses and allotypes: from structure to effector functions. Vidarsson et al. Frontiers in Immunology 2014 doi: 10.3389/fimmu.2014.00520
  • Luminex and its application for solid organ transplantation. Lachmann et al. Transfus Med Hemother 2013;40:182–189

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