Antibodies (immunoglobulins, Ig) are a special class of glycoproteins presented on the surface of B cells as membrane-bound receptors and in blood serum and tissue fluid as soluble molecules. Antibodies are the most important factors of specific humoral immunity. Antibodies are relatively large glycoproteins consisting of two identical heavy (H) chains, a hinge region, the CH2 and CH3 domains, and two identical light chains (L) (see inset figure). Five types of heavy chains (α, γ, δ, ε and μ) and two types of light chains (κ and λ) have been identified. Heavy chains are stably linked with carbohydrate chains. In mammals there are five classes of Ig – A, D, E, G and M – which are different in the structure and composition of the heavy chains and in their functions. Antibodies can exist as monomers (IgG, IgD, IgE, serum IgA) and as oligomers (secretory IgA is a dimer and IgM is a pentamer). IgG is the primary blood serum immunoglobulin of a healthy human (~ 75% of the total fraction) and includes 23% carbohydrates, two antigen-binding Fab fragments and one Fc (constant) fragment.
Antibodies are used by the immune system to identify and neutralize foreign objects and are responsible for the functions of the antigen-binding effect and the effector. As mentioned. IgG is the main serum immunoglobulin of a healthy human subject. In 1970, Najjar and Nishioka discovered that an enzymatic cleavage of IgG gave rise to the tetrapeptide TKPR (fragment 289-292 of the CH2 domain of the heavy chain), capable of stimulating the activity of macrophages. The researchers called this fragment tuftsina. The discovery of tuftsin, which possesses both immune-stimulating and neurotrophic activity, has been an impetus for the search for new biologically active peptides derived from antibodies. And it was already assumed that functional proteins could be a source of biologically active peptides. In the mid-1980s, peptides derived from the enzymatic hydrolysis of milk proteins (casomorphin, lactorphins, casoparan), hemoglobin (hemorphin and kyotorphins) and albumin (kinetensin) were discovered, and this discovery confirmed the ‘hypothesis. Initially, the production of such peptides in vivo seemed questionable, but the presence of tuftsin and hemorphin in humans and other mammals was later proven.
Tuftsin originates from a specific fraction of the parent protein through enzymatic processing. It has a broad spectrum of activities mainly related to the function of the immune system that it exerts on phagocytic cells, in particular on macrophages. These include the enhancement of various cellular functions such as phagocytosis, motility, immunogenic response, and bactericidal and tumoricidal activities. The characteristics of tuftsin, together with its low toxicity, make the peptide an attractive candidate for immunotherapy. The ability of tuftsin to increase cellular activation is mediated by specific receptors that have been identified, characterized and recently isolated from rabbit white blood cells. Tuftsin has been chemically synthesized with a variety of techniques; a multitude of analogues have also been synthesized and extensively studied. As a result, fragments of the IgG H chain produced as a result of enzymatic cleavage of IgG within the antigen-antibody complex were discovered, synthesized and studied. These fragments include rigin (341-344), immunorphine (364-373), immunocortin (11-20) and p24 peptide (335-358) with its fragments.
For at least thirty years, the group of Professor Navolotskaya of the Institute of Bio-organic Chemistry at the Russian Academy of Sciences has been intensely involved in the study of these substances. Immunorphin has been artificially synthesized and it has been shown that, like beta-endorphin itself, it is able to stimulate the growth of the human T-Jurkat lymphoma cell line. The opioid receptor antagonist naloxone does not block the stimulating effect of the peptides, indicating that they must necessarily bind to naloxone insensitive receptors. Immunocortin, on the other hand, stimulates the cells of the adrenal glands to synthesize steroid hormones (cortisol), through the same receptor for the hormone ACTH. Scholars suspect that this action serves as a countermeasure to stop the exaggerated immune reaction after it ends. In fact, it is well known that cortisol is an inhibitor of the functions of the immune system. The human IgG heavy chain sequence 369-373 – VKGFY – was named pentarphin. When added to macrophage cultures along with virulent bacterial strains of Salmonella typhimurium, pentarphin engulfs the bacteria present in the macrophages to completely destroy them within 6 hours.
Unfortunately, tuftsin and these peptides are susceptible to internal degradation and their half-life in the blood is not long. More stable derivatives have been synthesized for some years, which seem to have good efficacy in stimulating T cells against cancer cells. Not only that, both fluorescent (FTIC-Tuf) and gadolinium conjugated (Gd-DOTA-Tuf) derivatives have been produced to be used for the localization of inflammatory or tumor foci to be detected by magnetic resonance. This could be important for the creation of specific molecules based on tuftsin for the diagnosis or treatment of various diseases. This peptide, thanks to its interfered action on macrophages, could serve as a therapeutic for medical conditions where macrophages have a pathogenetic or perpetrating role. One of them is multiple sclerosis. The cerebral macrophages or microglia, in fact, is the cellular component that damages and “eats” the myelin of the nervous structures in this autoimmune syndrome, leading to demyelination. In this condition, the immune balance is shifted towards the Th1 lymphocyte component.
Conversely, infusion of tuftsin in mice with experimental multiple sclerosis (EAE) resulted in increased expression of GATA3, which is a transcription factor that drives the development of Th2 lymphocytes and the release of anti-inflammatory cytokines. Tuftsin easily crosses the blood brain barrier and reduces the severity of EAE symptoms and dramatically improves recovery in wild-type mice. Not only that, tuftisine in the brain appears to participate in pain control systems (analgesia), which could be a benefit for patients with this disease who have chronic pain or fatigue manifestations. Many MS treatments aim at suppressing the immune response. Some reagents act by inhibiting the activation of microglia and T cells and cause a downregulation of inflammatory cytokine production. These treatments ease the symptoms of MS through their anti-inflammatory effects. Tuftsin, however, appears to affect MS / EAE symptoms differently, shifting the immune response towards an anti-inflammatory phenotype.
Tuftsin appears to modulate T cell behaviors by enhancing Th2 cytokines and expanding Tregs, not simply by inhibiting the Th1 response. Thus tuftsin exerts its effect through a broader “modulation” of the immune system. Not only that, more recently it was discovered that tuftsin could promote axonal regeneration by acting on its putative receptor which appears to be the neuropilin-1 receptor protein. This small “piece” of antibody, therefore, has all the credentials to be anti-inflammatory, pain reliever, regenerating and immune modulating that could make it a natural weapon in the fight against multiple sclerosis. It is paradoxical, considering that an excess of antibodies or auto-antibodies typical of autoimmune diseases including multiple sclerosis, cannot tame the disease in all its cellular and inflammatory components. Or the secret is right here: the normal production of tuftsin prevents the natural appearance of multiple sclerosis. When this appears instead it could depend, among its mechanisms, on the defective formation of tuftsin due to incorrect “processing” of the antibodies.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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