Dmitri Popov. PhD, Radiobiology.

MD (Russia)

Advanced Medical Technology and Systems Inc. Canada.

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system.

They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes.

. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6,TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.

A group of transmembrane proteins, Toll-like

receptors (TLRs), play critical roles as pattern-recognition receptors.

TLR has common effects, such as inflammatory cytokine induction or upregulation of costimulatory molecule expression, but also has its specific function, exemplified by type I IFN-inducing ability.

Immunoadjuvant effects are not only critical in antimicrobial immunity but are also involved in manifestations of autoimmunity.

TLR agonists are now promising therapeutic tools for various immune disorders, including allergy and Acute and Chronic Radiation Disorders.

Tsuneyasu Kaisho, MD, PhD,a and Shizuo Akira, MD, PhDb,c Kanagawa and Osaka, Japan.

http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Therefore understanding molecularmechanisms on TLRs should be quite useful in the development of therapeutic strategy against allergy and autoimmune

Diseases include Acute and Chronic Radiation Diiseases . (J Allergy Clin Immunol2006;117:979-87.)

Host defense in mammals copes with pathogens through 2 types of immunity: innate and adaptive immunity.

Innate immunity functions as a pathogen sensor and pattern recognition sensor and contributes to the eradication of pathogens or autoimmune reactions and the establishment of adaptive immunity. These functions heavily depend on pattern-recognition receptors (PRRs).

Tsuneyasu Kaisho, MD, PhD,a and Shizuo Akira, MD, PhDb,c Kanagawa and Osaka, Japan.

http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Toll like receptors (TLRs), are featured by their potent ability to activate antigen-presenting cells (APCs).

Innate immune cells carry the molecules that can not only recognize the microorganisms or not self- patterns but can also trigger the signaling pathways, leading to production of inflammatory cytokines or type I IFNs.

TLRs can recognize common molecular structures detected in certain groups of microorganisms as non-self. These were originally called pathogen-associated molecular

patterns, but here we call them microorganism-associated molecular patterns (MAMPs)

TLRs can also recognize proteins. TLR5 recognizes a protein, flagellin, which is a component of the bacterial flagella. Some scientists in USSR ( from 1970) and later in USA reported that flagellin derivates could be effective radioprotective medical substance.

Autoantibodies that are commonly associated with systemic auto immune diseases — such as systemic lupus erythematosus (SLE),

scleroderma and Sjögren’s syndrome (BOX 1) — bind DNA, RNA or macromolecular complexes that contain DNA or RNA.

Intracellular autoantigens become ‘visible’ to the immune system when they accumulate on the plasma membrane during apoptotic cell death, necroptotic cell death, necrosis and subsequent uptake and processing by activated antigen-presenting cells (APCs) then leads to a loss of tolerance.

Radiation induced apoptosis or necroptosis or necrosis results in the cleavage of these molecules (by granzyme B, other proteases or nucleases2), thereby creating neo-epitopes that can be recognized as foreign by cells of the adaptive immune system.

Toll-like receptors in systemic autoimmune disease. Ann Marshak-Rothstein.

http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Neo-epitopes could also be generated by other forms of post-translational modification or by structural

modifications induced by environmental factors such as ionized radiation or UV radiation or High Frequency Radiation.

However, data continue to accumulate in support of the idea that auto-antigens are auto-antigens because they

are auto-adjuvants: that is, they have the capacity to activate the innate immune system directly and therefore promote self-directed immune responses. Utz, P. J., Gensler, T. J. & Anderson, P. Death, autoantigen modifications, and tolerance. Arthritis Res.

2, 101–114 (2000). 4. Plotz, P. H. The autoantibody repertoire: searching for order. Nature Rev. Immunol. 3, 73–78 (2003). Toll-like receptors in systemic autoimmune disease. Ann

Marshak-Rothstein.

Acute Radiation Syndromes is a complex of acute autoimmune, inflammatory disease that arises after different doses and different types of radiation and affect the hematopoietic system, central and peripheral nervous system, gastro-intestinal system, liver, skin, kidneys, lungs, vasculature, serous membranes and multiple organs. The effector mechanisms of inflammation depend on lymphocytes, neutrophils, monocytes, platelets and mast cells and involve the complement, kinin and coagulation cascades.

Toll-like receptors in systemic autoimmune disease. Ann Marshak-Rothstein.

http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Self –molecular ligands potentially contribute to autoantibody production with formation of immune complexes. Self -molecular ligands could play role of autoantigens.

Many of the common autoantigens are released from dead and dying cells, and might become available to the immune system as a result of excessive cell damage by radiation and an inability to appropriately clear apoptotic-cell debris.