Influenza: Diagnosis, Treatment, Prevention - V.D. Moskaliuk 2010

General information about influenza and other ARVI
The role of decreased immunological reactivity of the body in the development of ARVI

ARIs frequently develop against the Background of immunodeficiency states and significantly impact human health (K. Jakeman, H. Smith, C. Sweet, 1989; S.O. Kramariov, V.I. Maltsev, V.K. Kazymirko, 2003). The duration of the disease, the severity of its course, and The Development of complications depend on the functional state of The Immune System (H. Chen, K. Subbarao, D. Swayne et al., 1993; V.D. Moskalyuk, 2007).

The body's defense against infection consists of the sequential engagement of three distinct stages of protection against the pathogen: 1) natural resistance factors; 2) early inducible response (the first two belong to nonspecific pre-immune resistance mechanisms); 3) adaptive or acquired Immune Response (V.A. Isakov, M.G. Shamanova, R.N. Nasorina, 1995; A.P. Myronenko, O.V. Komohorov, P.M. Ostapchuk, 2001).

Natural resistance factors are engaged immediately after the pathogen breaches the Skin or mucous membranes and enters the internal environment of the body. Their action continues throughout the entire period of the body's fight against the infection, but they work most effectively During the first 4 hours following viral invasion, when they act as practically the body's only defenders.

Two powerful barriers stand in the way of a virus that has penetrated the body: cellular and humoral factors of natural resistance. The former include tissue macrophages (MΦ), neutrophils (NΦ), and natural killers (NK); the latter include natural IgG Antibodies and Complement (R.O. Day, G.G. Graham, A.O. Whelton, 2000).

Practically any virus that enters a macroorganism possesses The ability to induce the alternative complement activation pathway, resulting in the generation of C3a, C5a, C3b, and other fragments that act as pro-inflammatory mediators with chemotactic activity. They induce the accumulation of NΦ at the site of inflammation. The C3b fragment and natural IgG antibodies interact with the virus and opsonize it, thereby preparing the virus for engulfment by phagocytes. The first Cells that invading Viruses interact with upon entering the body's internal environment are tissue MΦ (G.J. Demmler, 2000; S.N. Turishev, 2002, 2004). They engulf opsonized viruses, destroy them (though not always), become activated, and synthesize cytokines. Opsonized viruses are captured and destroyed significantly more intensively by phagocytic cells than non-opsonized ones (Z.M. Tretiakevich, O.A. Lysenko, 2001).

Subsequently, as a rule, the second and more powerful echelon of the body's defense against infection comes into play—the early inducible response, which lasts for up to 96 hours until specific Immunity factors begin to function. It also comprises cellular and humoral factors. The former include activated MΦ, NΦ, and NK cells; the latter include cytokines and acute-phase Proteins (APPs) produced by Liver cells under METABOLISM/18.html">The Influence of these cytokines. Tissue MΦ, activated by viral Antigens generated during the phagocytosis of the pathogen, produce a series of cytokines (monokines)—tumor necrosis factor-alpha (TNF-α), interleukins 1ß, 8, and 12, α-IFN, etc., which exert an activating effect on new populations of cells migrating to the inflammation site: monocytes, NΦ, and NK cells. These Cell populations also begin to produce cytokines, recruiting increasingly more cells into the defense process. In addition, during viral Cleavage, microbial Peptides are formed, which the macrophage, in a complex with Class II Major Histocompatibility Complex molecules (MHC II), delivers to T-lymphocytes. This is a critical stage without which the development of specific immunity is impossible (V.M. Kozko, O.I. Mohylynets, H.I. Hradil, D.V. Katsapov, 2006).

The action of cytokines produced by MΦ during the early inducible response determines the primary mechanisms of anti-infective defense at the Initial Stages of the infectious process. The most important cytokine produced by activated MΦ during the early inducible response is IL-12. To look ahead slightly, The Nature of the immune response—specifically the predominant development of cellular or humoral immunity—depends on this cytokine. IL-12 activates monocytes/macrophages, NΦ, and NK cells. Phagocytes activated in this manner absorb viruses more intensively, destroy them faster, and digest them. Activated NK cells exhibit greater cytotoxic activity against pathogen-infected cells. IL-1, IL-6, TNF, IL-8, GM-CSF, and other cytokines produced by macrophages during the early inducible response are pro-inflammatory cytokines. Their action entirely determines the onset of the inflammatory process that develops when a virus penetrates a macroorganism. Specific Examples of cytokine Participation in the development of inflammation are well known (A.G. Azimov, 2002):

1. The elevation of body Temperature during infectious processes depends on the action of IL-1 and IL-6 on the Central Nervous system.

2. The synthesis of APPs (C-reactive protein, mannose-binding protein, etc.) depends on The Effect of IL-1 and IL-6 on liver cells. APPs possess a pronounced ability to opsonize viruses that have entered the body.

3. The Development of the classical signs of inflammation (edema, erythema, pain, heat) depends entirely on TNF.

4. Peripheral Blood leukocytosis as a characteristic sign of inflammation depends on GM-CSF, G-CSF, and M-CSF, which enhance the proliferation and differentiation of Bone Marrow precursor cells and accelerate their maturation into mature granulocytes—from 7 down to 1.5 days.

5. The migration of NΦ and monocytes to the inflammation site depends on α-chemokines (IL-8) and ß-chemokines, as well as on GM-CSF, which are potent Inducers of phagocyte motility.

At the site of inflammation, along with tissue macrophages—the primary initiators of inflammation—other cellular elements play a substantial role in combating the infection. These are primarily NΦ and NK cells (J.A. Meddlers, G.C. Wang, S. He, R.G. Webster, 1999).

The main defenders of the body against viruses at the stage of the early inducible response are neutrophils. They perform two important Functions: first, they engulf and destroy viruses. This process is dramatically enhanced upon opsonization of the pathogens (either by C3b + IgG or APPs) and upon the activation of neutrophils by cytokines produced by macrophages and NK cells. Second, they themselves are powerful producers of cytokines—IL-1ß, IL-8, IL-12, TNF-α, GM-CSF, α-IFN, platelet-activating factor (PAF), and fibroblast growth factor (FGF)—through which new echelons of cells arriving at the inflammation site are activated and recruited to fight the pathogen. FGF, produced by monocytes/macrophages and neutrophils, plays an important role in reparative processes by enhancing wound healing.

Natural resistance factors and the early inducible response are nonspecific and protect the body during the first 96 hours post-infection. Around this timeframe, the adaptive immune response begins to develop—that is, true specific immunity, which represents the final and most powerful echelon of the body's defense. It includes the development of protective immunity and immunological memory. Protective immunity is formed through the development of humoral and cellular immune responses.

The Essence of the humoral response lies in the generation of a population of B-lymphocytes that synthesize specific antibodies of the IgG, IgA, IgM, and IgE classes (N. Morishita, E. Nobusawa, K. Nakajima, S. Nakajima, 1996; A.S. Monto, D.P. Robinson, M.L. Herlocher et al., 1999).

The cellular response is The formation of a population of antigen-specific T-lymphocytes: Th1 and Th2 cells, cytotoxic T-lymphocytes, and delayed-type hypersensitivity T-effectors, which possess the ability to specifically recognize the antigen that triggered their appearance, interact with it, and perform various effector functions.

Immunological memory is driven by the formation of memory T- and B-cell populations. Their characteristic feature is rapid proliferation upon exposure to a specific antigen, resulting in the generation of a large population of effector cells and the corresponding synthesis of large amounts of antibodies and cytokines. Immunological memory can persist for years, and sometimes for a lifetime (smallpox, measles, and other infections). It forms The basis of post-vaccination immunity and serves as a highly effective defense against reinfection—that is, re-exposure to the same pathogen.

Thus, immunological memory, much like intellectual memory, develops and is not inherited. In other words, the immune system, much like the central nervous system, is capable of learning (J.E. McElhaney, G.S. Meneilly, K.E. Lechelt et al., 1993).

The adaptive immune response develops when the virus overcomes natural resistance factors and bacterial antigens accumulate in quantities sufficient to initiate an immune response. Any immune response can be divided into 4 phases: recognition, activation, proliferation, and differentiation.

In both cellular and humoral responses, recognition is a complex intercellular interaction between antigen-presenting cells (monocytes/macrophages, dendritic cells, B-lymphocytes) and T-helper cells. Antigen-presenting cells capture the antigen, break it down into peptide fragments using their enzymatic system, and display it on their surface in a complex with MHC II. Using its antigen-recognition receptor, a T-helper must recognize the peptides lying within the MHC II groove of the antigen-presenting cell. The CD4 receptor of the T-helper, located adjacent to the antigen-recognition receptor, must recognize the antigenic determinants of the antigen-presenting cell's MHC II. This is so-called double recognition, THE PRINCIPLE OF which is to ensure specific interaction within the immune response exclusively between autologous cells. The consequence of this is the formation of a complex between the T-helper and the antigen-presenting cell (M.K. Yerofeeva, V.L. Maksakova, A.S. Shadrin et al., 2000).

At the onset of the immune response, the most critical step is determining the pathway that T-helper development will follow. This development significantly depends on the cytokines present during the Cytology/cytology/16.html">Early stages of the immune response. Under the influence of IL-12 produced by macrophages and γ-IFN produced by NK lymphocytes, CD4 T cells differentiate into Th1 helpers, which are responsible for the development of the cellular immune response. The main cytokine produced by these cells is γ-IFN. Under the influence of IL-4, basophils, or eosinophils, CD4 T cells differentiate into Th2 helpers, which are responsible for the development of the HUMORAL IMMUNE RESPONSE. The main cytokines produced by these cells are IL-4, IL-5, IL-6, and IL-10 (M.K. Yerofeeva, V.L. Maksakova, I.L. Kolyvanova et al., 2003; W. Tan, X. Xiang, D. Qiu et al., 2003).

During the development of the humoral immune response, the surface immunoglobulin receptor of B-lymphocytes recognizes a soluble antigen; The Cell engulfs it, cleaves it into low-molecular-weight peptides, and delivers them in a complex with MHC II to Th2 helpers. The latter interact with viral peptides via the double recognition described above. This interaction activates both B cells and T cells. On T cells, this activation is manifested by the expression of a new antigenic receptor, CD154, for which a specific Ligand, CD40, exists on B cells. The CD154 + CD40 interaction serves as a powerful inducer for B-lymphocyte proliferation, which is significantly enhanced under the influence of IL-2. The cytokines IL-4, IL-5, IL-6, and IL-10 produced by Th2 helpers play a decisive role in immunoglobulin Gene switching and the Synthesis of the main classes of specific IMMUNOGLOBULINS—antibodies. They are required for The production of IgM, IgA, and IgE antibodies (S.A. Guryeva, 2002; M.K. Yerofeeva, V.L. Aksakova et al., 2003).

Antibodies play a vital role in protecting the body against viruses. This is manifested by the inhibition of viral interactions with epithelial Cells of the respiratory, urogenital, and gastrointestinal tracts (secretory IgA); the neutralization of viral and Other toxins and antigens (IgG); the opsonization of viruses (IgG and, to a lesser extent, IgA); and the lysis of viruses through the combined action of complement and IgM antibodies (S.A. Guryeva, 2002).

The humoral immune response plays a leading role in protecting the body against viral infections, especially at their early stages, preventing the virus from penetrating susceptible cells. This is the protective mechanism of polio vaccination, for example: antibodies formed after vaccination protect Spinal Cord Neurons from viral invasion. However, they play no protective role once the virus has entered a susceptible cell. Conversely, in the late stages of certain viral infections (RS virus infection, Influenza), antibodies can exert a negative effect on the body by forming immune complexes with viral antigens, which deposit in Tissues and cause damaging effects (S.A. Guryeva, 2002).

The key driver in developing a cellular immune response is the generation of antigen-specific CD4⁺ Th1 helper populations and antigen-specific, MHC-restricted CD8 cytotoxic T lymphocytes. As noted previously, the synthesis of Th1 cells is induced by IL-12 produced by macrophages. Among the cytokines secreted by Th1 helpers, IFN-y plays the most prominent role in cellular immunity; it is a potent activator of virtually all cell populations involved in anti-infective defense, with macrophage and NK cell activation being particularly critical for antiviral protection (I.S. Freydlin, 1995).

When cytotoxic T lymphocytes (CTLs) are generated, the antigen-presenting cell is typically a dendritic cell, which presents microbial peptides in complex with MHC class I determinants. The antigen-recognition receptor of the CD8 T lymphocyte must recognize this peptide, while the CD8 molecule located adjacent to the receptor recognizes the MHC class I determinants (dual recognition). The resulting complex is stabilized by the interaction of several costimulatory molecules. Of these, the most crucial is the recognition of the dendritic cell's CD80 receptor by the CD28 molecule on the T lymphocyte. This interaction triggers T lymphocyte activation, the appearance of the IL-2 receptor (CD25) on their surface, and moderate IL-2 synthesis. Driven by this cytokine, CTLs proliferate and significantly increase in number throughout the body. However, a CTL's own IL-2 is generally insufficient for robust proliferation, making activated Th cells (potentially primed by the same dendritic cell) the primary suppliers of IL-2 (I.S. Freydlin, 1998).

The primary function of CTLs in anti-infective defense is the elimination of cells infected with intracellular pathogens (viruses, Mycoplasmas, chlamydiae, mycobacteria, etc.). These target cells express viral peptides complexed with MHC class I determinants. Utilizing its antigen-recognition receptor and CD8 molecule, a CTL recognizes the virus-infected cell, forms a complex with it, and becomes activated. This triggers the release of granules containing cytotoxic proteins, such as perforin and granzymes (I.S. Freydlin, 1998).

Perforin has the ability to insert itself into the membrane of the target cell and form pores. Attempting to clear these pores through endocytosis, the cell inadvertently internalizes granzymes. The latter then induce apoptosis and the destruction of the affected cell.

In addition to secreting cytokines that "arm" other cells, Th1 helpers also directly participate in neutralizing viruses. Certain viruses, upon entering macrophages, can persist there for extended periods and even replicate. The surface of such cells may express viral peptides complexed with MHC class II antigens. A CD4 Th1 helper recognizes and interacts with this complex, resulting in macrophage activation and the destruction of the viruses (A.F. Frolov, V.M. Frolov, I.V. Loskutova, 2000).

Thus, There are two main pathways for combating viral infections: 1) the destruction of infected cells by CD8 CTLs, which halts viral Replication and consequently prevents their spread throughout the body; and 2) the activation of infected macrophages by CD4 Th1 cells, leading to the destruction of viruses within the phagolysosome.