Immune System Activation

Immunity overview
The immune system is the natural defense of the human body. It protects the host from a universe of exogenic invaders (viruses, pathogenic microbes) that are a permanent threat for the health and constantly change themselves in order to escape the natural body defense. The immune system also helps the host to eliminate toxic or allergenic substances that enter the body through mucosal surfaces. The ability of the immune system to recognize self from non-self and create proper response to an invading pathogen, toxin or allergen, is crucial. It uses both innate and adaptive mechanisms to detect and eliminate pathogenic microbes (Chaplin 2010).

Our environment contains a huge range of pathogenic microbes and toxic substances that challenge the host by a huge number of different pathogenic mechanisms. It is not surprising, therefore, that the immune system uses a complex array of protective mechanisms to control and usually eliminate these organisms and toxins. A general feature of the immune system is that these protective strategies rely on detecting structural features of the pathogen or toxin that mark it as distinct from host cells. Such host-pathogen or host-toxin differentiation is essential to allow the host to eliminate the threat without damaging its own cells and tissues (Chaplin 2010).

Innate immunity
The first set of responses constitutes the innate immune response. Innate immunity (also called natural or native immunity) provides the early line of defense against microbes. It consists of cellular and biochemical defense mechanisms that are ready to resist the pathogen immediately, preventing invasion. The mechanisms of innate immunity are specific for structures that are common to groups of related microbes and may not distinguish fine differences between them (www.creative-diagnostics.com). 

The principal components of innate immunity are (www.creative-diagnostics.com):

  1. Physical and chemical barriers, such as epithelia and antimicrobial chemicals produced at epithelial surfaces;
  2. Phagocytic cells (neutrophils, macrophages), dendritic cells, and natural killer (NK) cells and other innate lymphoid cells; 
  3. Blood proteins, including members of the complement system and other mediators of inflammation. 


Adaptive immunity
The second set of responses constitutes the adaptive immune response. Adaptive immunity (also called specific or acquired immunity) recognizes and reacts to a large number of microbial and nonmicrobial substances. The landmark ability of adaptive immunity is to recognize different pathogens, called specificity, and to respond more vigorously to repeated exposures to the same microbe, known as memory. The unique components of adaptive immunity are cells called lymphocytes and the proteins they produce, called antibodies. Foreign particles that induce specific immune responses or are recognized by lymphocytes or antibodies are called antigens (www.creative-diagnostics.com). 


Immunomodulation
Immunomodulation is the regulation and modulation of immunity either by enhancing or by reducing the immune response. Modulation of immune response may involve induction, expression or amplification of immune response. In other words, immunomodulation involves a change in the human body’s immune system caused by agents that activate or suppress its function (Shivaprasad 2006). The modulation in the immune system resulting in enhancement of the immune reaction, it is known as immunostimulation (Shivaprasad 2006).


Immunostimulators
Immunostimulants, also known as immunostimulators, are substances (drugs and nutrients) that stimulate the immune system by inducing activation or increasing activity of any of its components (Shahbazi 2016).

There are two main categories of immunostimulants (Kumar 2011):

  1. Specific immunostimulants provide antigenic specificity in immune response, such as vaccines.
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  2. Non-specific immunostimulants act irrespective of antigenic specificity to augment immune response to any antigen, or stimulate different components of the immune system. Examples are adjuvants and non-specific immunostimulators:

  • Adjuvants are a type of non-specific immunostimulant, often used in conjunction with vaccines. Administering an adjuvant along with a vaccine helps to generate a stronger protective response to the antigens in the vaccine, providing a better degree of protection against the pathogen. Many substances produced by the human body function as immunostimulants. 

  • Cytokines are a type of immunostimulants, which are produced by the cells of the immune system, and many of them enhance the immune function. Immunostimulant agents and immunosuppressant agents are very important and development of new effective substances of this class is in focus of the scientists all over the world in recent years. 

  • Bacterial products. Oral lyophilized extracts of bacteria species have been used since the early 1970s to improve symptoms and to prevent exacerbations in COPD patients. The value of these treatments, which are thought to be immunomodulating, is poorly understood (Steurer-Stey 2004). Among bacterial extracts we can include two major categories: compounds containing killed bacteria or chemical/mechanical bacterial lysates; compounds containing immunogenic components such as ribosomes and glycoproteins. Bacterial extracts are specific and non-specific stimulating agents, indicated for the prevention and treatment of respiratory infections, particularly acute and chronic bronchitis, pharyngitis, tonsillitis, laryngitis, rhinitis, sinusitis and otitis (Giovannini 2014). It is still not well understood how reliable bacterial extracts are in the prevention of the most common respiratory tract infections – viral infections (Roży 2008).They are used mainly for the prophyalxis of recurrent respiratory infections and are rarely administered in the acute phase.

  • Various synthetic agents are used as immunostimulative agents, such as levamisole, thalidomide and isoprinosine. Isoprinosine has been studied in Herpes simplex infections, subacute sclerosing panencephalitis, acute viral encephalitis caused by herpes simplex, infections caused by Epstein-Barr and measles viruses. The main challenge of isoprinosine is its safety profile. Some adverse effects related with Isoprinosine administration are well documented: Minor CNS depression, transient nausea and elevation of uric acid in serum and urine (Shahbazi 2016).Some ingredients of natural origin can offer safer, cheaper and in some cases - more effective, novel approaches in the immune system activation (Diasio 1996).

  • Complex carbohydrates. Several types of the complex carbohydrates have been studied, but the most popular are the glucans. Beta-glucans are naturally occurring polysaccharides. These glucose polymers are constituents of the cell wall of certain pathogenic bacteria and fungi. Beta-glucans increase host immune defense by activating complement system, enhancing macrophages and natural killer cells function. They can also prevent oncogenesis due to the protective effect against potent genotoxic carcinogens. As an immunostimulating agent, which acts through the activation of macrophages and NK cell cytotoxicity, beta-glucan can also inhibit tumor growth in its promotion stage. Broadly studied beta-glucans with significant scientific data available are yeast b-glucan and mushroom b-glucans (Akramiene 2007).

    EpiCor
    Epicor is a new generation imunostimulator produced by fermentation using the yeast Saccharomyces cerevisiae under patented technology. It contains b-glucan complex, proteins, peptides, antioxidants, polyphenols, organic acids, nucleotides and manans. The b-glucan from yeast has the strongest immunogenic effect as compared to the b-glucans of other origin, since it induces immune response at the lowest concentration. EpiCor exhibits proven effectiveness as shown in published research on humans. Patients who have administered EpiCor had statistically significant less episodes of flu-like symptoms, and those who got ill had statistically significant shorter duration of disease and milder symptoms (Moyad 2010). Patients with chronic pulmonary diseases have less frequent relapses while being on therapy with b-glucans (Vetvicka 2013).

    Shiitake extract
    Lentinus edodes (Shiitake) is a medicinal mushroom with a long tradition of use in Asia. The major active substance in L. edodes is a (1-6,1-3)-beta-glucan (lentinan). Beta-glucans activate cells of the innate immune response and modulate the secretion of inflammatory cytokines resulting in increased capability of the immune system for immediate reaction against pathogens (Kupfahl 2006). Lentinan given orally to elderly subjects was safe and induced an increase in the number of circulating B-cells (Gaullier 2011).

  • Probiotics. There is an increasing amount of evidence of the role of intestinal commensal bacteria in the development and modulation of the immune system. This led to great interest in the therapeutic potential of probiotics and other bacteria-based strategies for a range of immune-related disorders. Studies in animal models have identified strong immunomodulatory effects of many nonpathogenic bacteria and provided evidence that intestinal microbes can activate a common mucosal immune response and, thus, influence sites distant to the intestine, including the respiratory tract. Respiratory effects of probiotics in animal models have included attenuating allergic airway responses and protecting against respiratory pathogens. Dendritic cells appear central to directing the beneficial immune response to probiotic bacteria and in translating microbial signals from the innate to the adaptive immune system, whereas regulatory T cells are emerging as potential key effectors of probiotic-mediated responses, particularly in the reduction of allergic inflammation (Forsythe 2011).
    Daily dietary probiotic supplementation for 6 months was a safe and effective way to reduce fever, rhinorrhea, and cough incidence and duration and antibiotic prescription incidence, as well as the number of missed school days attributable to illness, for children 3 to 5 years of age. In this double-blind, placebo-controlled study, 326 eligible children (3–5 years of age) were assigned randomly to receive placebo, Lactobacillus acidophilus, or Lactobacillus acidophilus in combination with Bifidobacterium animalis subsp lactis(Leyer 2009).

    Streptococcus salivarius is an oral probiotic strain releasing two lantibiotics (salivaricin A2 and salivaricin B) that antagonize the growth of S. pyogenes, the most important bacterial cause of pharyngeal infections in humans also affected by episodes of acute otitis media. S. salivarius successfully colonizes the oral cavity, and has excellent safety profile. Prophylactic administration of S. salivarius to children with a history of recurrent oral streptococcal disease resulted in a considerable reduction of episodes of both streptococcal and viral infections and reduced the number of days under antibiotic and/or antipyretic therapy and days of absence from school or work (Di Pierro 2014).

  • Animal originated products have a potential application as immunostimulants, because they can be easily obtained, are not expensive and act against a broad spectrum of pathogens (Shahbazi 2016).

    Colostrum 
    Colostrum is the first maternal milk, which is produced during the initial three days after birth. In man it reaches around 200 ml for this three-day period. Its formulation is different from the maternal milk produced after these initial days, and contains higher concentrations of immunoglobulins, oligosaccharides and other factors which protect the newborn from diseases, since his or her immune system is still immature. The content of bovine and human colostrum are comparable, which allows to use bovine colostrum to improve the immune function in humans. It contains enzymes, antibodies (IgG1, IgG2, IgA, IgM) and growth factors, which stimulate the immune system (Stelwagen 2009).
    Effect of colostrum in humans:  The incidence of flu in individuals who have taken colostrum was lower, duration of disease was three times shorter and the overall number of flu episodes was four times lower in comparison with the vaccination group and the no-prophylaxis group. These differences between the groups were statistically significant (Cesarone 2007).
    In high-risk cardiovascular patients (end-stage coronary disease patients, patients with pulmonary hypertension or severe cardiovascular problems) the frequency of flu episodes was twice less in the colostrum group, and among the vaccinated patients who did not take colostrum there was even one case of severe flu with cardio-pulmonary complications which resulted in death (Cesarone 2007).     
    Intake of colostrum increases the level of sIgA, which is the main secretory immunoglobulin and first line of defense in the gastrointestinal mucosa (Patiroglu 2013).

  • Nutritional factors

    Vitamin D
    Vitamin D has attarcted attention recently for its pleiotropic actions on many chronic diseases. The importance of vitamin D on the regulation of cells of the immune system has gained increased appreciation over the past decade with the discovery of the vitamin D receptor (VDR) and key vitamin D metabolizing enzymes expressed by cells of the immune system. Animal studies, early epidemiologic and clinical studies have supported a potential role for vitamin D in maintaining immune system balance (Kamen 2018).
    Younger age and lower serum vitamin D levels were associated with increased risk of viral respiratory tract infections (RTI). Serum vit D levels <75 nmol/L increased the risk of viral RTI by 50% and levels <50 nmol/L increased the risk by 70% (Science 2013).

    Zinc
    It is well recognized that zinc is an essential trace element, influencing growth and affecting the development and integrity of the immune system. Scientific research has begun to reveal the molecular mechanisms underlying the action of zinc on the immune function. It is clear that this trace element has a broad impact on key immunity mediators, such as enzymes, thymic peptides and cytokines, explaining the paramount importance of zinc's status for the regulation of lymphoid cell activation, proliferation and apoptosis (Dardenne 2002). Zinc contributes to the normal function of the immune system (EFSA 2014) and decreases incidence of infections in elderly people (Prasad 2007).


HIGHLIGHTS

  • The immune system is the natural defense of human body. It protects the host from a universe of exogenic invaders (viruses, pathogenic microbes) that are a permanent threat for the health and constantly change themselves in order to escape the natural body defense. 
  • The immune system employs many potent defense mechanisms that have the ability to destroy a broad range of microbial cells and to clear a vast variety of both toxic and allergenic substances.
  • Immunostimulators, are substances (drugs and nutrients) that stimulate the immune system by inducing activation or increasing activity of any of its components
  • Novel approaches in the immune system activation based on optimal safety profile, cost-effectiveness and efficacy against wide range of pathogens, should be considered.
  • Some clinically studied ingredients of natural origin, which activate specific and non-specific immune response against wide range of pathogens, are: complex carbohydrates (Epicor, Extract of Shiitake, prebiotics), Probiotics, Animal originated products (Colostrum), Vitamin D and Zinc.

Reference

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