With a mass of 2 – 3 kg the immune system belongs to the large organs of the human organism. The immune cells and lymphatic tissue are distributed throughout the body. In addition to its complexity, the immune system has impressive dynamics in terms of cell division and cell death, organ remodelling through cell migration and emigration, changes through differentiation are the rule. The immune system is the most important organ for the integrity, individuality and health of the organism.
The classical division consists of a congenital and adaptive immune system.
The cells of the innate (non-specific) immune system
The cells of the innate immune system include macrophages and monocytes. In the tissues they have slightly different properties. Since the macrophages are located in all tissues, they are usually among the first to recognise and phagocytize invading pathogens. At the same time, the cells of the organism are warned and the secretion of cytokines, the messenger substances of the immune system, triggers the cascade of specific defence mechanisms.
Furthermore, polymorphonuclear granulocytes belong to the cells of the innate immune system. The neutrophils, basophilic and eosinophilic granulocytes are hardly found in the tissue, they are located in peripheral blood. In the case of infections, they are increasingly formed in the bone marrow and then brought in large numbers to the focus of inflammation. There they have specific tasks to perform.
Furthermore, mast cells are only found in the tissue (especially in the skin and mucous membranes). If they detect infectious agents or receive special activation stimuli (e.g. IgE), they release toxic substances within seconds. Through cytokine secretions, the mast cells are also able to attract further cells and develop inflammatory reactions.
The interdigitating dendritic cells (dendritic cells, DCs) migrate as immature cells from the blood into the tissues, where they form numerous tender branches. As Langerhans cells they form a dense network in the skin with the appendages. When activated by infectious agents, these cells stop pinocytizing and migrate with the lymph flow into the lymph nodes and present the antigens that they have absorbed into the tissue to the lymphocytes.
Another form are follicular dendritic cells (FDCs). They form a network in the B-cell follicles of the secondary lymphatic organs. They specialise in the uptake of antigenic substances that they reach with the lymph stream and present them to the B lymphocytes.
Natural killer (NK) cells are lymphocytes that specialise in killing infected cells, tumour cells and cells “labelled” by antibodies.
The cells of the adaptive (acquired, specific) immune system.
The cells of the adaptive immune system are lymphocytes with a large, almost round nucleus and a narrow cytoplasmic margin. B-lymphocytes and T-lymphocytes are distinguished. These cells are characterised by clonally distributed receptors for antigens. A clone is the offspring of a cell. This means that the antigen receptors of individual B and T lymphocytes differ from each other. The clonally distributed antigen receptors form the molecular basis of the extraordinary discrimination of the adaptive immune system.
The cells of the adaptive immune system are the B-lymphocytes and T-lymphocytes.
In humans, B-lymphocytes mature in bone marrow. The antigen receptors are called B-cell receptors. They are membrane-anchored immunoglobulins or antibodies. When B-lymphocytes are activated, they differentiate into plasma cells. These cells are specialized in synthesizing large amounts of immunoglobulins and secreting them in soluble form. A plasma cell can produce up to 2000 antibody molecules per second.
The T-lymphocytes are removed from the bone marrow and shaped in the thymus into T-helper cells and cytotoxic T-lymphocytes (CTLs). The T lymphocytes recognise their antigens through the clonally distributed T cell receptors (TCRs). T-helper cells optimize the immune response. For example, they can stimulate B-lymphocytes to produce antibodies and help macrophages to kill absorbed microorganisms. Regulatory T-helper cells (Treg) act in the opposite direction and suppress the immune response. They have the vital function of protecting the organism itself from attacks by the immune system and limiting immune reactions and thus the damage caused by aggressive effector mechanisms of the immune system. The CTLs are specialized in killing infected cells.
The innate and acquired immunoregulatory network of antigen presentation
The cells of the non-specific defence are essential for the function of T-helper cells.
The activation of antigen presenting cells (APC) such as macrophages, dendritic cells and antigen presenting B cells is a first necessary step to trigger an adaptive immune response.
T lymphocytes are required for the control of intracellular pathogens and for the activation of B lymphocytes against most antigens. T-lymphocytes recognise foreign antigens on peptide fragments that are bound to proteins of the main histo-compa-tibility complex (MHC).
Through the innate complement system, pathogens are also opsonised humorally using proteases in order to label them for destruction by phagocytes and thus support or “complement” the immune system. Monocytes are always present in the tissue and are converted into phagocytic macrophages in inflammation.
The reaction of macrophages to bacterial lipopolysaccharides (LPS) depends on the binding of CD14 (LPS receptor complex) to toll-like receptor 4 (TLR-4), which subsequently leads to the production of inflammation-promoting cytokines and chemokines, as well as the expression of costimulating molecules.
Chemokines attract further defence cells to the site of infection. Neutrophil granulocytes are activated by interleukin-8 (IL-8) and tumor necrosis factor- α (TNF -α). They are the first to cross the blood vessel walls and penetrate the inflammation area. Here they produce oxygen radicals and nitrogen monoxide (NO) as a weapon against intruders via respiratory burst. To provide hydrogen peroxide and superoxide anions, they have NADPH oxidases in their lysosomes. Dead neutrophil granulocytes with phagocyte residues therefore form the main component of the pus.
To prevent the inflammation from spreading, activated macrophages release TNF¬-α locally, which leads to blood clotting in the surrounding blood vessels. However, if a systemic release of TNF-α occurs as a result of sepsis, a consumption coagulopathy with multiorgan failure develops.
The cytokines (IL-1, IL-6) released by the phagocytes activate the acute-phase proteins, such as C-reactive protein (CRP). As a result, the body temperature rises. At the same time, in addition to the innate non-specific immune reaction, the specific reaction is also initiated by some macrophages and predominantly dendritic cells in the inflammatory region accept pathogens and their antigens and transport them to the regional lymph nodes in order to present them to the T lymphocytes.
These then cause the release of interleukins for the adaptive immune response. Natural killer cells (NK cells) are activated by released interferon-γ (IFN-γ) and cytokines (interleukin -12). At the same time, IFN-γ and IL-12 enhance the expression of MHC-I molecules on endogenous T cells to protect against attack by activated NK cells, and the expression of viral peptide fragments in the complex with MHC-I on infected cells to stimulate cytotoxic T¬ lymphocytes (CTLs).
There are immediate counter-regulations in regulatory systems to prevent overreactions. Such T-regulatory cells (Treg) secrete IL-2, labelled CD4-CD25-Treg, IL-I0, IL-4 and TGF-ß and CTL overexpression, CD28-Treg, IL-10 in the sense of suppression.
TR-I cells prevent uncontrolled overexpression already during the formation of Th1 and Th2 cells.
NK cells recognize foreign antigens even without MHC labeling, which makes them so important in the fight against carcinoma cells, because NK cells particularly attack cells that present a delayed to no MHC-I expression on the cell surface. Cancer cells produce IL-1O, TGF-ß and IDO indolamine-2,3-dioxygenase) to weaken Th1 cells at the cellular level. Increased PGE-2 levels suppress the immune system and in particular NK activity (Biesalski, nutritional medicine, 323). In addition, PGE-2 is required for angiogenesis.
Similar immunological conditions can be found in pregnancy. Here too, GM-CSF (granulocyte/monocyte colony stimulating factor) and IL-4 and IL-1O for suppression of Th1 reactions are elevated to protect the fetus! In addition, the placenta expresses p58 and p70 NK cell-inhibiting receptor proteins (KIR) in excess to avoid attack by maternal CTLs, NK cells. To further protect against maternal T-cell attacks, we find elevated levels of the enzyme indolamine-2,3-dioxygenase in the placenta, which degrade the amino acid tryptophan, which is necessary for the proliferation of T cells (Janeway 570 ff). Tryptophan is also the starting substance for serotonin synthesis in the CNS (neuroimmunological reaction).
Vitamin C activates in high concentration IFN-γ and blocks TNF-α, as well as IL-¬1 ß (HarteI, 2004).
IFN-γ and IL-12 increase NK cell activity up to 100-fold (Janeway, p.87). Activated CTLs selectively kill target cells that express viral or other intracellular cytoplasmic antigens (chlamydia, listeria, borrelia) in the complex with MHC-I on their surface.
To kill pathogenic bacteria, APC activates inf1ammatory CD4-Th1 cells for cellular immune response that react to MHC-II.
The extracellular humoral immune response is triggered by CD4-Th2 helper cells, which stimulate B lymphocytes to form specific antibodies.
Mature B cells carry immunoglobulin molecules (IgM, IgD, IgA, IgG, IgE) as antigen receptors on their surface and secrete immunoglobulins as soluble antibodies after activation, which enable the control of pathogens in the extracellular regions of the body.
T-lymphocytes are therefore of decisive importance for both humoral and cellular immune responses ( Janeway, 8.35 ).
Thl cells stimulate the cellular and Th2 cells via IL-10, D-5, D-4 and TGF-β via the production of IFN-γ, IL-12 and IL-2 to stimulate the humoral, extracellular immune response.
The cytokines secreted by Th1 and Th2 inhibit each other ( Janeway,8.422 ). Therefore, vaccination during an infection would be associated with devastating consequences and is therefore contraindicated!
To prevent an overshooting of an immune reaction, inhibitory transmembrane proteins such as CD22 in B cells and CTLA-4 (CD152) in T cells block signalling during antigen presentation in the lymph node.
CTLA-4 is similar to the costimulating molecule CD28 and thus slows down the signalling of the APC to the T-cell. At the same time, CTLA-4 activates the expression of IDO in the APC, which results in the degradation of tryptophan.
Killer-inhibiting receptor proteins ( KIR ) protect the body’s own cells from the attack of NK cells, among other things.
Intestinal Th3 cells secrete IL-4, IL-l0 and TGF-ß similar to Th2 cells to moderately inhibit Thl cells to achieve an antigen tolerance to intestinal bacteria. As a result, secretory IgA is formed as mucosa of associated antibodies. Therefore, the immune system of the mucosa reacts tolerantly to foreign antigens without inflammatory stimulus.
In addition, T-regulatory cells (Treg cells) prevent an overreaction of Thl cells and prevent autoimmune diseases.
Dendritic cells (DCs) express IL-10 and IL-4 in Peyer’s plaques, while they synthesize IFN-γ and IL-12 in peripheral lymph nodes.
In order to maintain the homeostasis of the lymphocyte population, the activated effector T cells that are no longer required are induced to apoptosis by interaction with the Fas ligand after infection.
Programmed cell death can be blocked by oncogene Bcl-2. Bcl-2 prevents the swelling induced by apoptosis and thus the cytochrome c from escaping from the mitochondria. Only the release of cytochrome c from the mitochondria of the cell triggers apoptosis, which makes carcinoma cells immortal, as they have hardly any mitochondria and their hemoxigenase is also strongly expressed to degrade cytochrome c.
APC, such as dendritic cells, macrophages and some B cells activate T lymphocytes in lymphatic tissues (lymph nodes) after binding via TLR-4 and CDl4 (LPS) receptors to the antigen with the exception of antigen-presenting B cells that bind antigens soluble with surface immunoglobulins. This T -lymphocyte activation and differentiation into Th1 and Th2 lymphocytes is strictly bound to MHC II glycoproteins in combination with a costimulating molecule, the B7 (CD 80/86) of the APC with binding to TZR and core receptor CD28 of the T cell. After activation, Th1 cells secrete IL-2, IFN-γ and TNF-α antagonistically to Th2 cells that predominantly express IL-10, IL-5, IL-4 and TGF-ß. To prevent an excessive immune reaction, CTLA-4 is released simultaneously as an inhibitory protein against Th1 and CD22 against Th2.
Cytokines of Th1 cells activate the cellular immune response via NK cells and CTL (MHC-I), while Th2 cells are responsible for humoral antibody formation.
List of abbreviations:
APC antigen-presenting cell
CD Nomenclature / cluster of differentiation
CD4 T4 lymphocytes
CD14 LPS and lipopolysaccharide-binding protein LBP
CD22 B-lymphocytes, conjugates of sialinsre
CD25 activated T-, B-cells, activated monocytes
CD28 T subpopulations, activated B lymphocytes
CTLA cytotoxic T-lymphocyte activation-associated protein
Cytochrome iron porphyrin proteins for electron transfer in the respiratory chain
Ocogenic DNA sequences in the genome of the cell with carcinogenic activity
Bcl-2 protein located in mitochondria,important in programmed apoptosis
TGF tissue growth factor
NADPH nicotinamide adenine dinucleotide phosphate
Treg regulatory T-helper cell
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