1. Radiation can modify self-antigens by damaging cells and DNA, which activates the immune system. 2. This activation leads to immune reactions that can cause cell death through apoptosis or necrosis. 3. The immune system then creates immunological memory to the self-antigens that were modified by radiation exposure, enabling a faster response upon subsequent exposures.

1. RADIATION PROTECTION:
IMMUNOLOGICAL MEMORY.
Dmitri Popov
MD (Russia), PhD (Russia, Canada)
Advanced Medical Technology and Systems Inc.
intervaccine@gmail.com

2. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Research Proposal: RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Dmitri Popov
• Full-text · Research Proposal · Jan 2015
• Add resources
• File name: Radiation and Self-Tolerance Mechanism..pptx
DOI: 10.13140/RG.2.1.4563.1765

3. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• General Definition:
• Immunological memory is the ability of the immune system to
respond more rapidly and effectively to pathogens that have been
encountered previously, and reflects the pre-existence of a clonally
expanded population of antigen-specific lymphocytes.

4. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Radiation Protection:
• Immunological memory created after irradiation, and is the ability of
the immune system to respond more rapidly and effectively to
different types and doses of radiation that have been encountered
previously, and reflects the pre-existence of a clonally expanded
population of antigen-specific lymphocytes.
• General mechanisms of creation of immunological memory to
radiation similar to mechanisms of creation of immunological
memory to different types of pathogens.

5. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• During an initial irradiation (or primary immune response) involving a T-
dependent antigen, naive follicular B cells are activated in the presence
of TFH cells within the follicles of secondary lymphoid organs
(i.e. spleen and lymph nodes) and undergo clonal expansion to produce
a foci of B cells that are specific for the antigen.
• Most of these clones differentiate into the plasma cells, also called effector
B cells which produce a first wave of protective antibodies and help clear
the infection, and fraction persist as dormant memory cells that survive in
the body on a long-term basis after having gone through a highly mutative
and selective germinal center reaction.
• https://en.wikipedia.org/wiki/Memory_B_cell

6. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Within germinal centers, B cells proliferate and mutate the genetic
region coding for their surface antibody (also known as
immunoglobulin).
• The process is called somatic hypermutation and is responsible for
introducing spontaneous mutations with a frequency of about 1 in
every 1600 cell division (a relatively high frequency considering the
low mutation frequency of other cells of the body being 1 in 106 cell
divisions).
• https://en.wikipedia.org/wiki/Memory_B_cell

7. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Then after gaining a set number of mutations, germinal center B cells
are subjected to a round of selection by TFH cells. B cell clones that
have mutated and gained higher affinity surface immunoglobulin that
better recognize antigen receive cellular contact-dependent survival
signals from interacting with their cognate TFH cells and go on to one
of three fates: (i) differentiate into plasma cells that have improved
affinity towards antigen (therefore more efficient than their earlier
the generation of plasma cells in clearing the infection), (ii) affinity
matured memory B cells, or (iii) retained in the germinal center to re-
enter another round of mutative replication and TFH cell-dependent
selection.
• https://en.wikipedia.org/wiki/Memory_B_cell

8. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Therefore, as an infection proceeds, memory B cells selected in the
later stages of a germinal center response are found to have
accumulated the highest numbers of immunoglobulin mutation
events with superior affinity towards their targeted antigen.
Conversely, during the course of a germinal center reaction, low
affinity or potentially auto-reactive germinal center B cell clones, or
those that have gained non-functional mutations are out-competed
by higher affinity clones and eventually undergo cellular apoptosis.
• https://en.wikipedia.org/wiki/Memory_B_cell

9. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• With each such subsequent exposure to the same antigen, the number of
different responding B cell clones increases to generate a polyclonal
response and effectively a greater number of memory B cells persist. Thus,
a stronger antibody response (i.e. higher titres of more diverse antibody
molecules) having improved affinity towards antigen is typically observed
in the secondary immune response. It is unclear at what stage such a
model reaches saturation to provide an optimal level of antibody-mediated
immune protection against the same antigen. However, the fact that all the
accumulation of cells of a single clone population express many of the one
same type of antibody and that these memory B cells survive for long
periods of time in a body underscores their functional significance
during vaccination and the administration of booster shots.
• https://en.wikipedia.org/wiki/Memory_B_cell

10. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Question number one:
• Mechanisms of creation of immunological memory to different types of pathogens well known.
• “The surface of every cell is covered with molecules that give it a unique set of characteristics.
These molecules are called antigens.
• Antigens are generally fragments of protein or carbohydrate molecules. There are millions of
different antigens and each one has a unique shape that can be recognised by the white blood
cells of your immune system. The white blood cells then produce antibodies to match the shape
of the antigens.
• The antigens on the surface of pathogenic cells are different from those on the surface of your
own cells. This enables your immune system to distinguish pathogens from cells that are part of
your body. Antigens are also found on the surface of foreign materials like pollen, pet hairs and
house dust where they can be responsible for triggering hay-fever or asthma attacks.”
• http://www.abpischools.org.uk/page/modules/infectiousdiseases_immunity/immunity2.cfm

11. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Question number one:
• Radiation induced immunological memory created to Radiation?
• Not at all.
• Radiation induced immunological memory created to self-antigens?
• Partially Yes.
• Radiation induced immunological memory created to damaged and
changed immunological properties of self-antigens?
• Yes.

12. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• “Ionizing radiation is a powerful cytotoxic force that can be
manipulated to specifically kill cancer cells at target sites. In addition
to the direct effect of radiation, focal radiation can have distant
bystander effects that influence tumor growth outside of the
irradiated region (Ohba et al., 1998).”

13. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• However, Ionizing radiation is a powerful cytotoxic force that non-
specifically kill all cells, and ionizing radiation cytotoxicity depend on
mitotic rates of cells and metabolic rate of cells.

14. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Leukocytes detect cell death through immune-based receptors for
molecules released by dying cells (often termed “danger signals”),
such as Toll-like receptor 4 (TLR4) and its ligands including the high-
mobility group box 1 protein (HMGB1; Apetoh et al., 2007).
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523399/

15. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Radiation Therapy clearly influences multiple immune-based
programs in tissues, some of which lead to durable tumor regression,
whereas others propel tumor development. It seems reasonable to
conclude that identifying pathways mediating activation of myeloid-
based pro-tumor immunity induced by RT, will encourage
development of novel therapeutics that suppress those activities to
effectively bolster RT responses.
• http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523399/

16. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Self-antigens.
• “The primary function of the immune system is to protect the host
from invasion by foreign organisms.
• But how does the immune system avoid mounting attacks against the
host organism? In other words, the immune system distinguish
between self and non-self antigens?”

17. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Autoimmune Diseases Result from the Generation of Immune Responses Against
Self-Antigens.
• Radiation Disease and Acute Radiation Syndromes could be considered as the
Generation of Immune Responses Against modified Self-Antigens.
• “Damage from ionizing radiation leads to effects on numerous cell
types within the self-microenvironment (SME).
• ALL (not only tumor cells) endothelial and epithelial cells are
sensitive to radiation, and the death of these cells initiates the
inflammation cascade.”

18. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Early radiobiological effect include : cells membrane damage, direct
dsDNA and ssDNA damage, indirect damage via proteases and DNase
activation, indirect damage via ROS and RNS creation and activation.
• A deoxyribonuclease (DNase, for short) is any enzyme that catalyzes
the hydrolytic cleavage of phosphodiester linkages in the DNA
backbone, thus degrading DNA.

19. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Inflammation
• Acute Radiation Disease (ARD) or Acute Radiation Syndromes (ARS)
are defined as the collective toxic clinical states observed from the
acute pathological processes in various doses of irradiated mammals;
to include: systemic inflammatory response syndrome (SIRS), toxic
multiple organ injury (TMOI), toxic multiple organ dysfunction
syndromes (TMODS), and finally, toxic multiple organ failure (TMOF).

20. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• Cell death.
• Apoptosis vs Necrosis.

21. RADIATION PROTECTION: IMMUNOLOGICAL
MEMORY.
• 1. Self-antigen modification.
• 2. ssDNA damage, dsDNA damage, cells membrane damage, immune
system activation, cytotoxic immune reactions, proteases activation
(intracellular –apoptosis; extracellular from WBC - necrosis, immune
cytotoxic complexes – cell necrosis), creation of immunological
memory to modified by radiation of self antigens.