Fundamentals of Immunology - Lecture Course by M. V. Skok - Kyiv 2002

Chapter III. Immune Processes at the Organism Level

Lecture 14. Pathologies of the Immune System

The Immune System is highly complex and meticulously regulated. However, as with any complex system, malfunctions and pathologies can occur. They can be broadly divided into:

1) inappropriate reactions to external Antigens;

2) autoimmune reactions; and

3) immunodeficiencies.

1. Inappropriate Reactions of the immune system.

1) Anaphylaxis and Allergy

For certain antigens, specific doses, and immunization schedules, a repeated exposure to the antigen triggers an immediate reaction accompanied by edema, convulsions, and vasoconstriction. This reaction can become fatal unless adrenaline is administered to relieve smooth Muscle spasm. Such a reaction may develop in response to certain medications—such as Antibiotics and anesthetics—as well as the venom of insects, snakes, and marine invertebrates. This type of response is referred to as anaphylaxis or anaphylactic Shock.

Certain external antigens provoke another type of inappropriate reaction, known as an allergy. Symptoms of allergy may include Skin itching and redness, rashes, tearing, and a runny Nose if the allergen enters the body via the respiratory tract (flower pollen, animal dander, dust, tobacco) or through the skin (cosmetics). Food allergens can induce diarrhea and vomiting.

The symptoms of both anaphylaxis and allergy are attributed to the effects of histamine, which is released by mast Cells upon stimulation by IgE-antigen immune complexes. The binding of immune complexes to the Fc_ε receptor triggers the phosphatidylinositol signaling pathway, which is accompanied by The production of arachidonic acid metabolites: Prostaglandins, Leukotrienes, and thromboxanes. The outcome of this signaling cascade is mast Cell degranulation, releasing histamine, serotonin, and heparin. These agents provoke local inflammation manifested as allergic symptoms. The reaction is essentially normal in mechanism, yet inappropriate in scale; rather than effectively eliminating the allergen, it inflicts damage upon the host Organism.

Allergy is hereditary and may be associated with specific Major Histocompatibility Complex types.

Methods for the Prevention and Treatment of allergic diseases include:

1) Avoidance of contact with the allergen.

2) Desensitization: administration of the allergen via an alternative route (e.g., subcutaneously) to stimulate the synthesis of Antibodies of a different Class (IgG), thereby preventing IgE from binding to the allergen.

3) Antihistamines (suprastin, tavegil, diazolin, claritin, etc.).

4) Steroid medications (hydrocortisone, prednisolone) for the generalized suppression of the Immune Response.

In recent years, more advanced approaches have been proposed:

- removal of IgE from the Blood via Immunosorption using anti-IgE antibodies;

- direct modulation of IL-4 synthesis, which stimulates immunoglobulin isotype switching from IgM to IgE.

2) Humoral cytotoxic immune reactions (antibody-dependent cell-mediated cytotoxicity).

These reactions cause damage to the body's own cells that bear a specific surface antigen. They proceed via two normal mechanisms:

- opsonization of the antigen presented on The Cell surface, followed by Complement-dependent lysis of the target cell;

- opsonization by antibodies, binding to Fc receptors on macrophages, natural killer cells, or CTLs, and subsequent cell-mediated lysis.

This principle underlies the destruction of foreign erythrocytes during blood transfusion and graft destruction if antibodies were already present prior to transplantation (hyperacute rejection). Certain types of autoimmune diseases (hemolytic anemia, Hashimoto's thyroiditis) trigger a similar response against self-antigens. The body reacts in the same way to certain medications. For instance, the sedative sedormid binds to Blood Cells (platelets) and induces the synthesis of antibodies that destroy platelets via complement-dependent lysis.

3) Formation of immune complexes.

The normal pathway for eliminating an antigen bound by antibodies involves The formation of soluble immune complexes that bind complement components and Fc receptors on blood cells and are cleared from the body by macrophages. Under conditions of antigen persistence (chronic infections) and specific antigen-antibody ratios, insoluble immune complexes form within the body, accumulating in Tissues and causing acute inflammation. This leads to high local concentrations of complement components and inflammatory mediators, microthrombus formation, and enhanced macrophage activity.

A number of pathological conditions develop through this mechanism.

1) Asthmatic Bronchitis in agricultural workers, pigeon fanciers, cheesemakers, and furriers: inhaled antigens bind to antibodies in the mucous membranes, and the immune complexes trigger a pathological reaction.

2) Rheumatoid Arthritis: antibodies against self-IgG are synthesized in the synovial fluid, and immune complexes accumulate in the joints, causing chronic inflammation.

3) Serum sickness. In cases of diphtheria, the administration of equine anti-diphtheria serum (antibodies) remains an effective treatment. Eight days post-injection, the patient develops antibodies against equine serum antigens. While antibody levels are low, immune complexes accumulate in the blood and tissues, accompanied by fever, lymphocytosis, and skin rashes; the joints, Kidneys, and Heart are also affected. As antibody titers rise, immune complexes become soluble and are efficiently cleared from the body—resulting in the patient's recovery.

4) Glomerulonephritis: immune complexes of a specific size clog

the capillaries in the renal glomeruli, initiating an inflammatory process.

4) Cell-mediated pathological immune reactions — delayed-type hypersensitivity.

Delayed-type hypersensitivity is a normal type of immune response involving CTL generation, but it is excessively intense, leading to damage to normal, healthy tissues. This mechanism underlies The Development of:

1) Mantoux test: when CTLs against tuberculosis pathogens are present in the body, the intradermal injection of attenuated mycobacteria triggers a local inflammatory reaction characterized by edema, redness, and itching;

2) Rashes in smallpox and measles, and herpes flare-ups: sites of eruption undergo intensive destruction of infected cells by cytotoxic T lymphocytes;

3) Chronic granulomas, such as in leprosy, and tuberculosis cavities in the Lungs: CTL accumulation leads to tissue necrosis;

4) Contact dermatitis: epidermal Langerhans cells present antigens (from cosmetics, Hair Dyes, and certain chemical compounds), triggering a cellular immune response with edema and microvesicles 12–15 hours later;

5) Insect stings.

5) Antibody-mediated autosensitization.

This phenomenon consists in antibodies that specifically bind to a receptor being able to activate the cell, effectively mimicking the action of a hormone, growth factor, or other signaling molecules. For example, thyrotoxicosis develops via this mechanism: autoantibodies to thyroid cell antigens stimulate these cells in the absence of the hormone.

2. Autoimmune diseases.

As noted in previous lectures, the price paid for the broad Specificity spectrum of T AND B lymphocytes is the real risk of autoimmunity. Tolerance to most autoantigens is established through a process of ignorance, meaning that potentially autospecific receptors are preserved. This applies more to B lymphocytes, since the control over T cell specificity is much stricter, given that T cells mediate the destruction of antigen-bearing cells and regulate the immune response. Autoantibodies are always present in the body at certain concentrations and are not necessarily harmful. It is even suggested that they may perform certain physiological Functions, such as aiding in the clearance of cellular debris. Autoantibodies invariably appear following necrotic processes and trauma when elevated levels of tissue antigens enter the bloodstream (myocardial infarction, traumatic Brain injury, gangrene). In some cases, they become drivers of pathological processes: chronic inflammation, immune complex diseases, and antibody-dependent cellular cytotoxicity. There is a fairly wide spectrum of autoimmune diseases, each characterized by its own Etiology and clinical course. Here are Examples of some of them.

1) Hashimoto's thyroiditis — antibodies to thyroglobulin.

2) Myasthenia gravis — antibodies to muscle acetylcholine receptors.

3) Juvenile diabetes — antibodies to pancreatic b-cells.

4) Rheumatoid arthritis — antibodies to IgG and cell nuclear antigens.

5) Systemic lupus erythematosus — antibodies to DNA and nucleoprotein.

6) Autoimmune Pemphigus - antibodies to skin Proteins.

Obviously, the appearance of autoantibodies in large quantities indicates impaired Regulation of the immune response. This is further evidenced by the increased incidence of certain cancers observed in autoimmune diseases. Autoimmune diseases are hereditary, meaning they are genetically determined. For example, the New Zealand Black (NZB) mouse strain is well known for invariably developing autoimmune hemolytic anemia at a certain age. It is believed that in this case, there is a defect in negative Selection, resulting in the survival of cells with a specific autospecificity.

There is no clear consensus regarding THE ORIGIN OF autoimmune diseases. The classical view states that autoimmunity develops when a self-antigen is modified and consequently recognized by the organism as foreign. In some cases, this hypothesis finds confirmation. For instance, alterations in the glycosylation pattern of IgG Fc fragments have been detected in rheumatoid arthritis, which can be classified as a Modification of the autoantigen.

In some instances, the cause of an autoimmune disease may be the cross-reactivity between self and foreign antigens. It is well known, for example, that autoantibodies attacking the myocardium in rheumatic fever are produced following a streptococcal infection and directed against streptococcal antigens. Recently, data have emerged indicating that antibodies against myelin basic protein, which are the main pathogenic factor in multiple sclerosis, are associated with Chlamydia infection.

Other proposed causes of autoimmune diseases include the presence of a second allele of the TCR $\alpha$-chain and The phenomenon of determinant spreading. The presence of two specificity receptors on a single T cell carries the risk of simultaneous activation of two response specificities, one of which may be autoreactive. The expansion of the response repertoire as it develops ("determinant spreading") has been observed experimentally when immunization with a peptide epitope of a protein possessing a recipient-analog led to the appearance of antibodies against other epitopes of that antigen. In such cases, the involvement of the autoantigen in the Propagation of the response is evident.

According to the "self-ignorance" concept, potentially autoreactive cells remain quiescent until the autoantigen appears in sufficient quantity and is properly presented. Obviously, this can be facilitated by destructive processes and infections that act as polyclonal activators of the immune system and induce the necessary level of costimulatory signal expression. A special role may be played by superantigens (bacterial endotoxins), which nonspecifically activate T cells bearing certain T-cell receptor families.

It should be noted that the pathologies of well-known autoimmune diseases are predominantly antibody-mediated. This further confirms that control over T-cell specificity (and especially CTLs) is much stricter compared to the control of B-cell specificity.

Diagnostic methods for autoimmune diseases include tests for the presence of specific antibodies. Treatment approaches include general immunosuppressive therapy (Steroids, immunosuppressants) as well as several specific strategies:

- plasmapheresis: extraction of the patient's blood, Separation into plasma and formed elements, and return of only the formed elements to the body—antibodies present in the plasma are removed;

- immunoadsorption, where autoantibodies are selectively removed from the blood.

These approaches provide rapid relief of the patient's condition, but only temporarily, until new batches of autoantibodies are synthesized.

- administration of competing Peptides—peptide epitopes of the autoantigen that "trap" autoantibodies and specific T-helper cells;

- a modification of this approach is the administration of peptide-MHC Structure/178.html">Protein Complexes, which compete more effectively with the autoantigens presented on cells;

- attempts are being made to induce apoptosis in autoimmune cells.

3. Immunodeficiencies.

Immunodeficiencies can be classified into primary (congenital) and secondary (acquired).

Congenital immunodeficiencies can impair all branches of specific and nonspecific Immunity. Their causes are defects in specific genes leading to deficiencies in:

- The Complement System;

- myeloid cell development (impruing macrophage and monocyte functions);

- B lymphocytes (underdevelopment, improper differentiation) - leading to agammaglobulinemia (absence of antibodies); the response to viral infections develops normally;

- T lymphocytes (Thymus underdevelopment) - absence of cellular immunity reactions. Such immunodeficiencies are often associated with a defect in the purine nucleoside phosphorylase Gene;

- stem cells; in this case, all immune systems are affected.

Acquired immunodeficiencies develop during an individual's lifetime under the Influence of External factors. Such factors may include:

1) nutritional quality, in particular, the level of iron entering the body with food;

2) viral or bacterial infection, which can lead to immunosuppression;

3) radioactive irradiation (including ultraviolet and X-rays), which primarily affects the immune system: with The Emergence of the immune system, organisms become radiosensitive (the hagfish withstands a 10 times higher radiation dose than the lamprey); the loss of Radioresistance is the price paid for the Evolution of the immune system;

4) stress;

5) corticosteroids;

6) malignant diseases;

7) viral infection that specifically targets the immune system (AIDS).