IMMUNOLOGY TEXTBOOK - Mercury Podillya 2013

MECHANISMS OF IMMUNE DEFENSE IN BACTERIAL, VIRAL, FUNGAL, AND PROTOZOAN INFECTIONS

One of the primary Functions of The Immune System is to recognize and destroy bodies and substances bearing foreign Genetic information, including infectious disease pathogens. The Development of anti-infective resistance involves both specific and nonspecific mechanisms. Their interaction follows a specific temporal sequence and is characterized by synergistic mutual enhancement.

In cases of suspected infection, the Immune Response may manifest as:

1) a normal inflammatory response (in this case, immune system correction is not recommended);

2) a hyporeactive state (in this case, correction is necessary);

3) a hyperreactive state (in this case, correction is also necessary, but with a different focus than in a hyporeactive state).

A decrease in the indicators of one or more immune system links (no more than 30% compared to normal), accompanied by the reactivity of its other links in response to antigen contact in a previously healthy individual, is termed immune dysfunction. When immune dysfunction is present, the reactions of other immune components prove sufficient for partial neutralization of the antigen (infectious factor) or deceleration of the inflammation it caused, leading to patient recovery or the Transition of acute inflammation into a chronic form. When such dysfunction is present, the Diagnosis indicates the specific immune link that proved hyporeactive in response to the infectious agent.

Microorganisms can be conventionally divided into extracellular and intracellular.

Nonspecific Immunity. The Skin and mucous membranes serve as the primary barrier preventing pathogens from entering the host Organism. Desquamation of keratinized epithelium, the presence of Fatty acids on the skin, sebaceous gland secretions, the cleansing function of the ciliated epithelium of mucous membranes, and the presence of Lysozyme along with bacterial and viral multiplication inhibitors in secretions ensure the destruction of pathogens. However, the principal defense mechanism is phagocytosis. At the same time, not all engulfed Cells perish; for instance, mycobacteria, brucellae, salmonellae, and listeria can not only survive within phagocytes but in some cases multiply there. Certain Bacteria (capsular forms of pneumococci) are phagocytosed with difficulty or not at all.

Cellular mechanisms of resistance are combined with humoral factors, such as lysozyme, interferon, and the alternative Complement activation pathway. The latter reaction is triggered by bacteria, Viruses, Fungi, and endotoxins, developing immediately after the invasion of the infectious agent.

Specific immunity. Since microorganisms possess diverse antigenic determinants, a polyclonal immune response develops in the body after a certain period. The portal of entry and the CHARACTERISTICS OF THE pathogen determine whether cellular or humoral immune reactivity will be deployed. The invasion of extracellularly multiplying pathogens typically induces humoral immunity, whereas Infections caused by intracellularly replicating pathogens induce Cell-mediated immunity.

The duration of immune protection can be lifelong (measles, pertussis) or limited (Influenza). In both cases, long-lived immunological memory cells are responsible for this.

Thus, four stages can be distinguished in the development of specific anti-infective immunity: 1) induction (afferent) stage; 2) immunoregulatory (proliferative) stage; 3) effector (productive) stage; 4) stage of immunological memory formation (Table 30).

Class="center">Table 30. Characteristics of the stages of anti-infective immunity (according to N. V. Medunitsyn)

Characteristics of Immunity in Bacterial Infections

The immune system operates stereotypically, utilizing the same Mechanisms for the recognition, destruction, and elimination of foreign Antigens. Microorganisms can be conventionally subdivided into extracellular and intracellular.

Immune Response to extracellular microorganism invasion. The immune response directed against extracellular parasitic bacteria (staphylococci, streptococci, clostridia, diphtheria pathogens, intestinal infections, etc.), as well as certain large viruses (measles, poliomyelitis), pursues two goals: the elimination of the pathogens themselves and the neutralization of their toxins.

Neutrophils, which ensure the phagocytosis of microorganisms, are the main effector cells in the fight against extracellular pathogens (bacteria). The engulfing and bactericidal functions of neutrophils are sharply enhanced in the presence of complement and IgG. These neutrophil functions are activated by TNF-α, IL-1β, IL-6, and other cytokines produced by macrophages, natural killer (NK) cells, and T lymphocytes.

Thus, an important component of DEFENSE AGAINST EXTRACELLULAR forms of infectious agents consists of nonspecific resistance factors, among which the two main ones play a leading role: The Complement System and the mononuclear phagocyte system (phagocytic cells).

The primary effector function of specific humoral immunity in defense against extracellular pathogens (bacteria) is carried out by antigen-specific Antibodies synthesized by plasma cells (class M, G, and A IMMUNOGLOBULINS). The participation of antibodies as an effector link in immune defense is realized in 3 forms: neutralization of the pathogen and its toxins (antibody-dependent cell-mediated cytotoxicity reaction); complement activation; and opsonization, which helps restrict the pathogen's spread.

Specific antibodies (immunoglobulins) bind to the bacterial surface and, in the presence of complement, induce cytotoxic reactions (bacteriolysis). Furthermore, bacteria coated with antibodies or complement are more readily phagocytosed (opsonized).

B lymphocytes, T helper cells (CD4 T lymphocytes), and antigen-presenting cells (APCs) participate in the realization of such a response. Specific T-cell receptors (TcR) are capable of recognizing a foreign antigen only in a complex with self-cell antigens of the Major Histocompatibility Complex (MHC) On the surface of accessory antigen-presenting cells. The body's professional APCs include macrophages, dendritic cells, and B lymphocytes. Their roles in various TYPES OF IMMUNE responses are not identical. For instance, in the HUMORAL IMMUNE RESPONSE, B lymphocytes predominantly perform the APC function. B lymphocytes can recognize antigens in solution and bind protein, polysaccharide, and lipoprotein soluble antigens using specific IgM receptors (as well as CR1 receptors for the C3b complement component, which in turn may be bound to the microbe), whereas CD4 T lymphocytes can only recognize short peptide fragments of protein antigens in a complex with class II MHC molecules.

Thus, for a T lymphocyte to recognize an antigen and become activated, antigen "processing" with MHC II by the antigen-presenting cell is required. In this process, the antigen is phagocytosed by the antigen-presenting cell (APC) and cleaved in an acidic environment by phagolysosomes. Among the resulting fragments, Selection occurs based on The ability to complex with MHC II molecules pre-synthesized in The Endoplasmic reticulum of the same cell. A specialized molecule—a chaperone—transports MHC II into the endosome, where its complex with the peptide is formed and subsequently presented on The Cell membrane. The antigenic peptide-MHC II complex is recognized by the TcR with the participation of the CD4 coreceptor molecule (of the T lymphocyte). An additional activation signal for the CD4 T lymphocyte is provided by IL-1β, which is released by the activated antigen-presenting cell. IL-1β is produced by many Cells of the body in response to infection, the action of microbial toxins, inflammatory agents, certain other cytokines, and activated complement components; it has the ability to stimulate T and B lymphocytes, increase The production of acute-phase Proteins by hepatocytes, stimulate the production and secretion of other cytokines by various cells, and enhance cellular proliferation.

Following activation resulting from antigen recognition, a CD4 T lymphocyte differentiates into a T helper cell (Th). Furthermore, in the humoral immune response directed against extracellular pathogens, inflammatory reactions occur within loose Connective Tissue. These involve basophils and mast cells, which release interleukin-4 (IL-4) upon activation. In the presence of IL-4, CD4 T cells (Th0) differentiate into type 2 T helper cells (Th2) and begin to synthesize IL-4 themselves, which acts as a primary growth factor for both Th2 and B lymphocytes. As a result, a Th2 clone is generated, capable of activating specific B cells that have bound the specific antigen responsible for triggering the immune response. During this process, Th2 cells recognize the antigen associated with MHC class II via the CD4 receptor, with CD40L and CD40 serving as adhesion molecules. The second signal required for B cell activation is IL-4 secreted by Th2 cells, alongside the necessary presence of an antigen-bound immunoglobulin receptor on the B cell membrane. Specific B cells activated by type 2 T helpers begin to vigorously produce matching antigen-specific antibodies, known as immunoglobulins.

Antibodies can participate in the elimination of infectious agents through several mechanisms: opsonization of bacteria and enhancement of their phagocytosis via phagocytic FcR and CR1 receptors; neutralization of bacterial exotoxins; and activation of the complement system, leading to the action of its membrane attack complex. In addition, specific IgA class antibodies present on mucosal surfaces (sIgA) prevent bacterial colonization of mucosal surfaces and play a role in neutralizing their toxins.

The establishment of sanogenetic (recovery) mechanisms in various bacterial infections underlies Specific features of the immunity that develops during the course of such diseases.

Thus, in bacterial infections whose causative agents produce exotoxins (such as diphtheria, tetanus, botulism, and gas gangrene), the primary role in immunity formation is played by antibodies generated within the body (antitoxins). The interaction between an antitoxin molecule and a toxin molecule can lead to several outcomes:

- blockade of the receptor-binding site of the toxin molecule, thereby limiting toxin fixation on target cell receptors;

- direct neutralization of the catalytic (enzymatic, toxic) domain of the toxin molecule;

- formation of an immune complex resulting in the neutralization of the toxic, receptor-binding, and/or translocation domains (subunits) of the toxin. Such complexes are phagocytosed and degraded by host cells. However, antitoxic antibodies do not block bacterial adhesion to target cell surfaces or subsequent colonization. Consequently, artificial antitoxic immunity does not provide complete host protection and fails to prevent bacterial fixation on target cell surfaces, cellular and tissue colonization, or bacterial proliferation.

In cases where pathognomonic pathogens produce exotoxins (such as tetanus or diphtheria), antitoxins readily neutralize these toxic substances; however, during a primary infection, they may be synthesized too late to effectively protect the organism.

It should be noted that bacterial infection is accompanied by the release of large amounts of bacterial endotoxin, which can suppress antibody production and neutrophil phagocytic activity (leading to a carrier state or chronic foci of infection). Massive influx of endotoxin and microorganisms into the bloodstream (the so-called superantigen effect) triggers hyperactivation of macrophages, along with activation of the complement system and type 1 and 2 T helper cells independently of immune response Specificity, resulting in a systemic inflammatory response clinically manifested as Shock (bacterial shock).

In another group of bacterial infections (such as meningococcal disease, pertussis, and legionellosis), immune lysis and phagocytosis of bacteria play the decisive role. IgG antibodies produced during these infections initiate a series of antibody-mediated biological reactions:

a) upon antibody fixation on the bacterial surface, the classical complement pathway is activated, resulting in The formation of the membrane attack complex and subsequent lysis of exposed bacterial membrane areas;

b) opsonization of bacteria by antibodies, followed by the interaction of antibody Fc fragments with macrophage Fc receptors, which enhances the phagocyte's engulfment and digestive capacity;

c) fixation of the resulting bacterial Ag-Ab-C 1,4,2,3b complex onto macrophage C3b receptors, which also boosts the phagocytic uptake of such complexes;

d) neutralization by antibodies of bacterial anti-phagins—factors that prevent pseudopodia formation by phagocytes, inhibit macrophage migration, or form part of bacterial anatomical structures (such as streptococcal M protein, pneumococcal capsular Polysaccharides, etc.).

Thus, the immunity formed during meningococcal infection, pertussis, or legionellosis depends on circulating IgG levels, the concentration and activity of complement components, and the functional state of phagocytes.

The phagocytic and bactericidal functions of neutrophils are dramatically enhanced in the presence of complement and IgG. These neutrophil functions are activated by TNF-α, IL-1β, IL-6, and other cytokines produced by macrophages, natural killer (NK) cells, and T lymphocytes.

During an adequate immune response to bacterial infection, the immunogram exhibits the following changes: marked leukocytosis; elevated ESR; presence of toxic granulation in neutrophils (TGN); a shift of the leukocyte formula to the left; B lymphocytosis; elevated levels of class M and G immunoglobulins and circulating immune complexes (CICs); increased neutrophil phagocytic activity (phagocytic number, phagocytic index) and bactericidal capacity (NBT test); a pronounced increase in acute-phase proteins (CRP, complement components such as CH50); and, when an inflammatory response develops on mucosal surfaces, elevated immunoglobulin A.

As Examples, let us examine immunogram variants from patients with acute bacterial infections exhibiting either a normal immune response or immune dysfunction.

Patient S., aged 34, presented with acute furunculosis affecting the scalp, trunk, and lower extremities (Table 31).

Immunogram: during the acute phase of a bacterial (streptococcal) infection, the patient showed moderate neutrophilic leukocytosis, relative lymphocytopenia, and an elevated ESR. Complement levels were elevated. Neutrophil phagocytic activity and spontaneous bactericidal capacity were activated, accompanied by an inadequate functional reserve of the neutrophil oxidation-reduction potential (NBT test). Levels of circulating immune complexes (CICs) and class M (IgM) and G (IgG) immunoglobulins were elevated.

Diagnosis: acute furunculosis of the scalp, trunk, and lower extremities.

Conclusion: signs of humoral immune system activation and dysregulation of the macrophage link.

Table 31. Immunogram of patient S., 34 years old

Overall, the state of the immune system corresponds to an acute infectious-inflammatory process, with a reaction adequate to the presence of an extracellular infection. Culture of the furuncle content yielded Staphylococcus aureus susceptible to doxycycline and azithromycin. The patient was prescribed etiotropic antibiotic therapy: azithromycin 0.5 g daily intravenously for 3 days (total course dose of 1.5 g). The prognosis for the resolution of the acute inflammatory process in this particular case was favorable and did not require the administration of Immunomodulatory therapy.

Patient T., 29 years old, presented with Complaints of severe weakness, fever up to febrile levels (t = 39.8°), and a cough producing mucopurulent sputum streaked with Blood. She has a history of Chronic Bronchitis over the past 7 years, with exacerbations occurring 1–2 times a year. The latest deterioration followed hypothermia 2 days ago.

Sputum analysis: viscous, leukocytes 20-30 per high-power field, no mycobacteria isolated. Sputum culture revealed Str. pneumoniae, susceptible to Cephalosporins and macrolides.

Chest X-ray: on the right, inferior to the line extending from the spine of the scapula downward and laterally to the 10th rib along the mid-axillary line and terminating at the 4th rib along the mid-clavicular line, There is a diffuse homogeneous opacification merging with the Diaphragm; in the remaining lung tissue on the right and left, increased transparency of the lung tissue, slight decrease in lung transparency along the Bronchi, and enhanced pulmonary vascular markings are observed.

Conclusion: lower-lobe right-sided Pneumonia. Signs of diffuse pneumosclerosis and pulmonary emphysema.

Diagnosis: community-acquired right-sided lower-lobe pneumonia, clinical group 2. Chronic bronchitis, acute exacerbation. Diffuse pneumosclerosis. Pulmonary emphysema. Stage II respiratory failure. Immune system dysfunction with quantitative and functional T-cell deficiency.

Immunogram (Table 32): low hemoglobin and erythrocyte levels, elevated ESR, neutrophilic leukocytosis with a stab shift, marked lymphopenia, stage 1 endotoxemia. High engulfment and spontaneous bactericidal activity of neutrophils (phagocytic index, phagocytic number, spontaneous NBT test). High levels of circulating immune complexes (CICs) and immunoglobulins of all studied classes. Decreased absolute count of T-lymphocytes (CD3) and their antigen-induced activity (LST).

Conclusion: anemia, neutrophilic leukocytosis with signs of neutrophil hyperactivation, endogenous intoxication. Quantitative and functional T-cell deficiency against the Background of absolute lymphopenia. High CIC levels, hyperimmunoglobulinemia.

Based on the specific features of her immunological status, patient T. was prescribed the following regimen of immunotropic and etiotropic therapy for pneumonia:

1) etiotropic antibacterial therapy — ceftriaxone 1.0 g IV twice daily, azithromycin 0.5 g daily for 3 days IV (course dose 1.5 g);

2) detoxification therapy — reosorbilact 200 mL IV infusion, physiological saline 400 mL IV infusion twice daily;

3) immunofan 1 mL IM daily, № 10;

4) normal human immunoglobulin for intravenous administration 100 mL IV infusion once daily, № 5.

Immunorehabilitation:

5) cycloferon 12.5 mg SC twice a week, № 10.

6) sodium nucleinate 0.1 g 3 times a day.

Table 32. Immunogram of Patient T., 29 years old

Patient R., 32 years old, presented with general weakness, fever up to febrile levels (t = 38.6°), and pain in the left lower leg that started on the 2nd day after an unknown insect bite. Upon examination, the left lower leg is significantly enlarged, edematous, the skin is taut and has a "glossy" appearance, local Temperature in the left lower leg area is markedly elevated compared to the right, the leg is extremely tender upon Palpation, and regional lymphadenopathy is noted. The patient was examined by a surgeon and diagnosed with soft tissue Phlegmon of the left lower leg. Immune system dysfunction of the phagocytic type. Functional deficiency of the T-cell link (Table 33).

Immunogram: neutrophilic leukocytosis with a stab shift, relative lymphocytopenia. Low engulfment activity of neutrophils (PN, PI), increased spontaneous bactericidal activity (NBTspon.). Decreased antigen-induced activity of T-lymphocytes (LST).

Conclusion: neutrophilic leukocytosis with signs of phagocytosis dysregulation. Functional deficiency of the T-cell link.

Based on the specific features of patient R.'s immunological status, the following regimen of immunotropic and etiotropic therapy was prescribed for soft tissue phlegmon:

1) etiotropic antibacterial therapy — ceftriaxone 1.0 g IV twice daily, levofloxacin 500 mg IV infusion daily, metragyl 100 mg IV infusion once daily, for 5 days;

2) detoxification therapy — reosorbilact 200 mL IV infusion once daily for 5 days;

3) galavit 200 mg SC once daily, № 5;

4) thymalin 1 mL IM once daily, № 10.

Immunorehabilitation:

5) polyoxidonium 6 mg subcutaneously once daily, № 10;

6) sodium nucleinate 0.1 orally 3 times a day for 2 weeks.

Table 33. Immunogram of patient R., aged 32

Patient D., aged 23, presented with complaints of a sore throat that developed after hypothermia (getting his feet wet), general weakness, and a low-grade fever (t = 37.2°C). He was examined by an ENT specialist and diagnosed with acute Exacerbation of chronic laryngopharyngitis, immune system dysregulation with decreased functional activity of neutrophils, and dysimmunoglobulinemia.

Immunogram (Table 34): decreased functional reserve of the neutrophil oxidation-reduction potential (NBT-res.). Increased levels of class A immunoglobulins.

Conclusion: signs of decreased functional activity of the neutrophil link, dysimmunoglobulinemia.

Based on the immunological profile of patient D., the following course of immunotropic and etiotropic therapy was prescribed for laryngopharyngitis: 1) etiotropic antibacterial therapy — amoxicillin 500 mg 3 times a day for 4-5 days, or azithromycin 0.5 g on the first day, followed by 0.25 g once daily for 2-5 days. Bioparox — oropharyngeal spray 2 times a day for 5 days; 2) licopid 10 mg once daily for 10 days; 3) UV irradiation of the Tonsils, 5 sessions.

Immunorehabilitation: 4) ribomunyl 1 tablet 2 times a day, 4 days a week, course duration — 6 weeks, or respibron accordingly.

Table 34. Immunogram of patient D., aged 23

The presented examples demonstrate the diagnostic value of the immunological tests performed in terms of understanding the cause and nature of inflammatory processes, as well as guiding further patient management tactics. The compensatory capacities of the immune system are exceptionally large, and they can facilitate the resolution of a pathological process in a specific individual with altered immunological parameters even without any immunotropic therapy. The immune status identified in patient S. falls within a conditional norm. In contrast, for patient M., a conditional norm is out of the question due to the revealed immune system dysregulation accompanied by quantitative and functional T-cell deficiency, which ultimately led to a breakdown in the body's defense against microbes and predisposed the patient to infectious diseases. The same applies to patients R. and D. In all three cases of immune system dysregulation, combination immunotherapy is indicated.

When Pseudomonas aeruginosa, Proteus, or Staphylococcus epidermidis are isolated from patients, there is typically a decrease in the levels of B-cells, T-cells, and their regulatory subpopulations. When Escherichia coli or Staphylococcus aureus are cultured, In addition to B-cell deficiency, a pathognomonic hyperproduction of classes M and A immunoglobulins is observed. These data substantiate the hypothesis that a pronounced deficiency of major immune system links promotes the proliferation of pathogenic microorganisms within the infection focus, whereas a more favorable state of immune reactivity in a patient leads to the accumulation of non-pathogenic microflora.

A similar pattern is observed in women with acute Inflammatory Diseases of the uterine appendages. When opportunistic microflora is isolated, the predominant features are a decrease in the functional activity and count of T-lymphocytes, alongside an excessive lysozyme level. The combination of opportunistic microflora with gonococci is accompanied by lysozyme excess, suppression of RBTL, and activation of neutrophil engulfing function. Finally, opportunistic pathogens and Campylobacter induce suppression of RBTL and T-cell levels, as well as hyperproduction of IgM.

In cholecystitis, The Nature of immune disorders is fundamentally different. It is manifested by the hyperproduction of major immunoglobulin classes and a deficit in T-cell counts, with the severity of damage increasing as the condition progresses.

In non-specific cervicitis, which is another example of non-specific infection, patients exhibit a decrease in T-cells, B-lymphocytes, and a minimal overproduction of IgA, indicating an ongoing immune system imbalance. Soft tissue purulent infection causes alterations in other marker parameters, specifically RBTL (with PHA); the pathological process suppresses the functional activity of T-cells, increases B-lymphocyte counts, and depresses T-helper cell numbers.

In calculous and non-calculous Pyelonephritis, respective variants lead to a different form of immune disorders. Thus, in the former case, changes involve the T-cell and phagocytic links, whereas in the latter, they involve both T- and B-immune mechanisms.

Progressive exacerbation of the inflammatory process is accompanied by an increase in the degree of alterations in immune parameters. In campylobacter dysbiosis, stimulation of B-cells and a drop in T-suppressor and T-helper cell levels are observed. It is difficult to determine what comes first: whether the development of specific immune disorders triggers dysbiosis, or whether dysbiosis dictates the pattern of immune alterations.

In nasal carriage of pathogenic staphylococci, the predominant findings are a 2nd-degree deficiency in IgG concentration, total lymphocytes, and T-cells. In post-appendectomy patients, a characteristic feature is decreased IgG production, an excessive amount of IgM, and a deficit of total lymphocytes.

Investigation of cellular and humoral immunity parameters in frequently ill children also reveals deviations from reference values. These primarily include a drop in total T-cell, T-lymphocyte, and T-helper counts, a decrease in secretory IgA concentration, low lysozyme activity in nasal secretions, and a reduction in leukocyte interferon-producing capacity. However, depending on the presence of concomitant pathology, certain specific features emerge within the pattern of immune disorders.

Specifically, frequently ill children without concomitant pathology and those with allergies predominantly suffer from Impairment of the cellular immune link, which manifests as a decrease in the count of T-helpers, active T-cells, and T-suppressors. In children with ENT disorders and those with tuberculosis infection, an imbalance of the T-cell immune link develops, as evidenced by a simultaneous drop in T-helpers and active T-lymphocytes alongside elevated T-suppressor levels.

The combination of ENT pathology and allergies results in a reduced number of T-helpers and active T-lymphocytes coupled with IgM hyperproduction. Finally, in overweight children, the pattern of immune disorders changes fundamentally: the counts of total T-cells and IgA are diminished.

Thus, it is evident that there is a correlation between The Nature and severity of immune disorders, non-specific anti-infectious resistance, and the type of infection, its Clinical presentation, disease severity, chronicity tendency, comorbid conditions, complications, absence of certain peripheral immune Organs, isolated microflora characteristics, and excess body weight. This reflects the existence of stereotyped mechanisms of immune reactivity alterations driven by the aforementioned and other factors.

The obtained data hold both theoretical and practical significance because, on the one hand, they partially elucidate the Pathogenesis of diseases and, on the other hand, they refine disease diagnosis and suggest the development of targeted immunocorrection in the course of infectious pathology.