IMMUNOLOGY TEXTBOOK - Mercury Podillia 2013

STRUCTURE AND PRINCIPLES OF THE IMMUNE SYSTEM

Specific Immunity

Acquired specific (adaptive) Immunity is mediated by lymphocytes.

There is currently no universally accepted Classification of the Cells that execute specific immune responses. Based on their functional characteristics, several Cell types are distinguished:

- antigen-presenting cells (APCs), which capture Antigens, process them, and present the corresponding antigenic determinants to other immunocompetent cells (APCs include dendritic cells, monocytes and macrophages, as well as B-lymphocytes);

- effector cells, which directly carry out specific immune responses (effector immunocompetent cells include cytotoxic T-lymphocytes (CTLs) and plasma cells);

- regulatory cells, which ensure the activation or suppression of specific links in immune responses (activators include T-helper Inducers, T-suppressor inducers, type 1 T-helpers, type 2 T-helpers, and macrophages; inhibitors include T-suppressors; T-counter-suppressors render T-helpers insensitive to T-suppressors);

- memory cells, which retain information about previous encounters with a specific antigen, thereby facilitating a more robust Immune Response upon subsequent exposure.

The Functions of APCs include: 1) capturing native (unmodified) antigenic material via phagocytosis, pinocytosis, or receptor-mediated endocytosis; 2) partial proteolysis (Processing) of endogenous material within endosomes for 30–60 minutes at low pH, releasing antigenic epitopes (an epitope being the part of an antigen that interacts with the paratope, i.e., the hypervariable region of an antibody); 3) synthesis of glycoprotein molecules of the MHC (Major Histocompatibility Complex), also known in humans as the HLA system (Human Leukocyte Antigens), and binding of these synthesized MHC molecules to antigen epitopes; 4) transporting the MHC molecule/antigen epitope complexes to the APC surface, where they are presented to lymphocytes capable of recognizing them; 5) expressing additional (costimulatory) molecules on The Cell surface alongside the MHC/antigen complex to enhance interaction with lymphocytes; 6) secreting soluble mediators (predominantly IL1) that trigger lymphocyte activation.

There are two primary forms of specific immune responses: humoral and cellular.

Humoral specific immunity is mediated through The production of specific Antibodies in response to a foreign antigen. B-lymphocytes play The Central Role in executing the humoral response, differentiating into antibody-producing cells under antigenic stimulation. However, B-lymphocytes typically require assistance from T-helpers and antigen-presenting cells.

During The Development of a humoral response, a B-lymphocyte may acquire a microbial peptide via several pathways:

- Uptake of a soluble antigen from the surrounding microenvironment. The peptide requires no additional processing, as this has already been performed by another cell. This results in antigen-driven Selection of the B-lymphocyte(s) carrying pre-existing γ-globulin receptors on their surface that are most specific to the given antigen.

- Uptake of a soluble antigen via a γ-globulin receptor, followed by its intracellular processing within the B-lymphocyte and subsequent expression on the B-lymphocyte membrane in a complex with Class II MHC.

- Acquisition of an antigen from the macrophage surface, selection of B-lymphocytes via γ-receptors, Processing of the antigen within the B-lymphocytes, and its presentation to T-lymphocytes.

The macrophage class II MHC presents the antigen to a T-helper cell (CD4). Stimulated by IL-4 produced by neutrophils, mast cells, basophils, and eosinophils, the T-helper differentiates into a type 2 T-helper, which induces a HUMORAL IMMUNE RESPONSE. The most important interleukins produced by these lymphocytes are IL-4, IL-5, IL-6, and IL-10, which strongly stimulate the proliferation of the selected B-lymphocytes. Antibodies synthesized by the transformed B-lymphocytes (plasmacytes) are specific to the given antigen. The humoral response is particularly crucial against extracellular microbes, as antibodies enhance their uptake and destruction by phagocytes.

A defining feature of specific immunity is that T- and B-lymphocytes are equipped with specialized tools—antigen-recognizing receptors (class I and II MHC)—which enable the recognition of antigens and the differentiation between self and non-self. Subsequently, when necessary, mechanisms are engaged to produce antibodies (IMMUNOGLOBULINS) or killer T-lymphocytes specific to the antigens that triggered their formation.

A distinct form of specific immune response following contact with a foreign antigen is the establishment of immunological memory, which develops as the immune reaction subsides. Immunological memory refers to the body's ability to respond to a repeat encounter with the same antigen through a secondary immune response, which is faster and stronger.

This form of immune response is associated with the accumulation of a clone of long-lived memory cells capable of recognizing the antigen and mounting an accelerated and amplified response upon re-exposure.

Cellular (cell-mediated) specific immunity is mediated by the accumulation within the body of a clone of T-lymphocytes bearing antigen-recognition receptors specific to the given antigen. These cells are responsible for cellular reactions of immune inflammation and delayed-type hypersensitivity, in which macrophages participate alongside T-lymphocytes.

The T-cell immune system eliminates antigens presented on cells through the direct interaction of cytotoxic T-lymphocytes (CD8 T-cells, T-killers) with altered self-cells or foreign cells.

Another distinctive characteristic of T-lymphocytes relates to how they recognize antigens: T-lymphocytes do not recognize the antigenic peptide on its own, but rather its complex with class I or class II MHC molecules.

When an antigen forms a complex involving class I MHC molecules, recognition and destruction are carried out by cytotoxic CD8 T-lymphocytes.

Conversely, when an antigen forms a complex with class II MHC molecules, type 1 or type 2 CD4 T-helpers engage in interaction with this complex.

The Features of the cellular immune response are as follows:

- the triggering link in The formation of the cellular immune response is the production of interleukin IL-12 by a macrophage within which antigen processing takes place;

- the membrane of mature T lymphocytes features an MHC class I antigen-recognition receptor with an antigen Specificity that is independent of whether the Organism has previously encountered the given antigen;

- the encounter between a T lymphocyte and an antigen includes a stage of antigen-dependent T lymphocyte differentiation (unlike the antigen-independent differentiation that occurred in the Thymus);

- recognition of the specific antigen leads to T lymphocyte activation and its subsequent proliferation, culminating in the appearance within the organism of a large population (clone) of T lymphocytes with a specific reactivity capable of mounting a specific immune response.

To recognize a large foreign cell (such as a bacterium or virus) or an autologous Structure, T lymphocytes require an intermediate stage in which a macrophage or other antigen-presenting cell specially "prepares" the foreign material for recognition. This preparation process is termed processing (Digestion) and consists of the Enzymatic Cleavage of the foreign material engulfed by the macrophage. The individual blocks resulting from processing, or Peptides, are amino acid residues of a specific length representing epitopes of the foreign antigen. These peptides are recognized by T lymphocytes via their MHC class I antigen-recognition receptors the moment they reach the macrophage membrane in association with MHC class I molecules.

The T lymphocyte subpopulation bearing the CD8+ differentiation cluster on its surface belongs to T killers/suppressors. This dual name indicates that this T lymphocyte subpopulation can differentiate either into a T killer (cytotoxic T lymphocyte) or a T suppressor, performing different functions depending on the physiological needs of the organism.

The CD8+ T killer is the primary effector cell of cell-mediated immunity, which lyses target cells and ensures the genetic constancy of the organism's internal environment. CD8+ lymphocytes perform cytotoxic functions, participate in allograft rejection mechanisms and autoimmune reactions, and destroy virus-infected and tumor cells.

In the peripheral Blood and Secondary Lymphoid Organs, the CD8+ T killer exists in a resting state—the so-called mature resting cell. For it to differentiate into a mature T killer capable of exerting a killing effect, it is necessary for the CD8+ T cell to recognize a foreign antigen via its MHC class I receptor on an antigen-presenting cell and to generate a clone of specific T killers capable of delivering a cytotoxic effect.

To recognize a foreign antigen, the CD8+ T cell possesses a T-cell antigen-recognition receptor complexed with the CD3 structure. The CD8+ T cell (killer) recognizes not the whole foreign antigen, but rather specific blocks known as dominant peptides located On the surface of the antigen-presenting cell (macrophage or dendritic cell) in combination with MHC class I molecules. Exogenous peptides generated from intracellular parasites and Viruses are presented via MHC class I molecules. The CD8+ T cell (killer) performs a censor function, enabling The Immune System to monitor the constancy of the internal environment of the organism.

The MHC class II of an antigen-presenting cell (macrophage or dendritic cell) presents a peptide (antigen) to a T helper cell (CD4). Under METABOLISM/18.html">The Influence of IL-12 produced by the same macrophage, the T helper cell transforms into a type 1 T helper.

Upon recognizing the foreign peptide, the CD8+ T cell (killer) must receive an additional signal from the CD4+ cell (helper) that enables it to divide, resulting in the formation of a clone (group) of cells sharing the same specificity and executing the cellular immune response.

IFN-γ is the most critical cytokine secreted by type 1 T helpers. It activates the contact between the CD8 T killer and the MHC class I receptor of the macrophage presenting the same antigen. Type 1 T helper cells secreting IL-2 stimulate the proliferation of antigen-specific T cytotoxic lymphocytes (T killers).

The main function of T killers in anti-infectious defense is the destruction of somatic cells harboring pathogens intracellularly, while displaying the MHC class I – pathogen antigen complex on their surface. Upon direct contact with such a cell, the T killer releases granules containing the Proteins perforin and granzyme. Perforin inserts into the somatic cell membrane, forms channel-like "pores," and acts as a membrane-attack protein. Granzyme (Serine proteases) induces apoptosis and the subsequent death of the somatic cell along with the microbes contained within it.

CD4+ T helper lymphocytes can recognize a foreign peptide if it is located on The surface of antigen-presenting cells (APCs)—such as monocytes-macrophages, B lymphocytes, and dendritic cells—in association with MHC class II. APCs possess The ability to engulf foreign material entering the organism, process it using Enzymes by cleaving the antigen into peptide blocks, and then transport these peptides from the cell interior to the surface in combination with MHC class II molecules. Subsequently, the CD4+ T helper lymphocyte can recognize the foreign, typically exogenous peptide, triggering the activation and proliferation of CD4+ cells followed by their differentiation into type 1 or type 2 T helpers, which regulate the immune response.

Type 1 T helpers produce INF-γ, IL-2, and TNF-β. These cytokines activate macrophages and NK cells and promote the maturation of cytotoxic T killers, thereby driving a predominantly cellular immune response, particularly in intracellular and viral infections. The activity of type 1 T helpers predominates in patients with multiple sclerosis, Insulin-dependent Diabetes Mellitus, autoimmune thyroiditis, Crohn's disease, acute allograft rejection, and frequently in recurrent Pregnancy loss.

Type 2 T helpers produce IL-4, IL-5, IL-10, and IL-13, which govern the humoral response, particularly IgE production. Furthermore, IL-10 exerts an inhibitory effect on type 1 T helpers. The activity of type 2 T helpers is elevated during normal pregnancy and transplant tolerance, as well as in pathological conditions such as idiopathic pulmonary fibrosis, progressive systemic sclerosis, rapidly progressive HIV infection, and allergic disorders.

An alternative form of specific immune response is the development of immunological tolerance, defined as a lack of responsiveness to the organism's own antigens (autoantigens). This tolerance is acquired during embryonic development when functionally immature lymphocytes, potentially capable of recognizing self-antigens, encounter these antigens in the thymus, leading to their destruction or inactivation (negative selection).

In postnatal life, tolerance is induced by an antigen dose exceeding the conventional immunogenic threshold; that is, the higher the antigen dose, the greater the degree of tolerance and the longer it persists. However, in adults, tolerance to protein antigens can be induced at doses either above or below the immunizing dose. Low-zone tolerance corresponds to unresponsiveness in the T helper population, whereas high-zone tolerance reflects specific unresponsiveness at the level of both T helper and B cell populations.

Both antigen-specific (strictly immunological) and antigen-non-specific factors (non-specific reactivity) contribute to the preservation and Maintenance of the organism's antigenic Homeostasis (Table 2).

Table 2. Mechanisms of maintenance of antigenic homeostasis

Pathological or "stress-level" immune reactions lead to the development of pathology:

■ Hypersensitivity—an exaggerated immune ("immunity") response to allergen antigens, which causes Two Types of disorders: allergic disorders caused by exogenous allergens (allergy); and autoallergic (autoimmune) disorders caused by endogenous, self-Biomolecules (autoallergy). In autoallergic (autoimmune) diseases, "self" molecules are recognized as "foreign" by the immune system, triggering adverse reactions against them.

■ Anergy, defined as a lack of responsiveness to infectious agents (a variant of tolerance), can be a cause of infections resulting from deficient anti-infectious immunity.

Immune reactions are always aimed at maintaining the organism's phenotypic homeostasis and eliminating foreign molecules, yet they are accompanied by damage to the body's own Tissues—inflammation. However, these are not the sole manifestations of the immune system's functions, which are characterized by a constant "Background" level of activity. At the physiological level, the immune system operates continuously, generating new cells, immunoglobulins, and cytokines; its "background" physiological functioning is supported by stimulation from microorganisms (viruses, bacteria, Fungi) that persistently colonize the Skin and mucous membranes. Active interaction with them, their constant elimination, the Prevention of their generalization, and "surveillance" over them form the foundation of a healthy organism and serve as an indicator of the normal eliminatory function of the immune system.

Anti-infectious acquired (adaptive) immunity develops over the course of a lifetime As a result of stimulation of immune system cells by microbial antigens or through the receipt of preformed immune factors. Therefore, it can be natural or artificial, each of which may be further categorized as active or passive.

Natural active immunity arises as a result of contact with a pathogen (either after recovering from a disease or following an asymptomatic subclinical contact).

Natural passive immunity occurs as a result of The transfer of preformed protective factors—such as lymphocytes, antibodies, and cytokines—from mother to fetus across the Placenta (transplacental) or through breast milk.

Artificial active immunity is induced following the administration of Vaccines containing microorganisms or their constituent antigens.

Artificial passive immunity is established following the Introduction of preformed antibodies or immune cells into the body. Such antibodies are contained in the blood serum of immunized Donors or animals.

KEY FEATURES OF acquired immunity:

■ specific to a particular pathogen (bacterium, virus);

■ specificity depends on the presence of immune T and B memory cells bearing specific receptors and/or on the presence of circulating antibodies;

■ becomes enhanced upon repeated encounters with the pathogen;

■ may be accompanied by hypersensitivity (allergy) to the pathogen;

■ develops after the immune system contacts the pathogen, accompanied (or not) by Clinical symptoms of the disease; can be induced by appropriate vaccines.