Immune system

The Immune System (also known as the Immunlological System) is made up of all the mechanisms through which a multicellular organism defends itself from internal invaders such as bacteria, viruses or parasites.

The immune system can be divided into two main branches:

• The innate or non-specific immune system, consisting of physical and chemical barriers such as skin, gastric acid, mucus or tears as well as cells and active mechanisms such as phagocytes, natural killer cells and the complement system
• The adaptive immune system, with antigen-specific activity by T cells and specific antibody production by B cells.

This division is useful for categorizing the different components of the immune system, but it is important to recognize that in the immune response there is continuous interplay between members of both branches.

Innate Non-specific Mechanisms

The innate system is comprised of all the mechanisms that defend an organism in non-specific form, against an invader, responding in the same fashion, regardless of what it is. It constitutes older defense strategies, some of these being found in primitive multicellular forms, in plant and fungi.

Physical Barriers

• The skin is the first and main line of defense. The surface is made up of dead skin cells rich in keratin, which impedes microorganisms from entering the body. Lightly acidic and lipidic secretions from sebaceous gland and sweat glands create a hostile cutaneous environment impeding the excessive growth of bacteria.
• Gastric acid is a powerful defense against invading bacteria from the intestines. Few species are able to survive the low pH and destructive enzymes that exist in the stomach.
• Saliva and tears contain antibacterial enzymes, such as Lysozyme, which destroy the cellular walls of bacteria.
• In the intestines, the bacterial flora compete with one another and non-commensal pathogens for food and space, diminishing the probability of pathogenic bacteria multiplying in sufficient numbers to cause illness. For this reason the excessive ingestion of oral antibiotics can lead to the depletion of benign bacteria in the intestine. Upon ending treatment, dangerous species can multiply without any competition, thereby causing many illnesses.
• Mucus is another defense, coating the mucous membranes. It catches and immobilizes invading bodies, its composition is deadly to many microorganisms. It also contains Type Iga antibodies (which are a component of the adaptive immune system).

Phagocytes

Phagocytes are cells, such as neutrophils and macrophages, that have the capacity to directionally extend cellular portions (pseudopod), engulfing and overtaking a foreign particle or microorganism. This microorganism is contained inside a vacuole which is then merges with lysosomes, vacuoles rich in enzymes and acids, which digest the particle or organism. Phagocytes react to cytokines produced by lymphocytes, but also patrol the body autonomously , without stimulus, albeit in a less eficient manner. This form of defense is important against bacterial infections, as viruses typically have their own means of entering host cells and the majority of parasites too large to be consumed. Phagocytosis is also an important part of the cleaning process after cellular destruction following infection or any other process that leads to cellular death. Should many phagocytes die after phagocytosis, both phagocytes and bacteria can be trapped in a pasty liquid rich in stuctural proteins, known as pus.

Some bacteria, such as Mycobacterium tuberculosis, which causes tuberculosis, have defense mechanisms against digestion after phagocytosis, and survive within the phagocyte undetectable by lymphocytes.

Phagocytes and related cells:

• Neutrophil granulocyte: the most abundant type of phagocyte and is always the first to arrive at the scene of infection. Along with its lysosomal enzymes, it destroys foreign substances or kills pathogens with its "respiratory burst." The neutrophil respiratory burst is a chain of reactions that produces hydrogen peroxide, which almost immediately releases its oxygen ion to form hypochlorite by combining with surrounding chloride ions. Hydrogen peroxide, with its release of oxygen ion, and hypochlorite, are strong oxidizing agents which accomplish destruction of foreign substances and pathogens. For this respiratory burst, the neutrophil increases its oxygen uptake a hundred fold. Niacin (as NADPH) is also essential in the reaction.
• Macrophages: a gigantic cell, the mature form of a monocyte, has the capacity to consume many more bacteria than a neutrophil. Differentiation is stimulated through cytokine. It is more efficient in destroying bacteria than neutrophils, but lives for a shorter amount of time, having to be reformed through monocytes during each infection. It has its own respiratory burst, releasing nitric oxide from arginine. Nitric oxide and chemicals that arise from it, particularly peroxynitrite, can kill viruses, bacteria, fungi, protozoa, some helminths, and tumor cells. With this powerful mechanism, the only reason sickness still occurs is because it could not function fully.
• Basophil granulocyte and Mast Cells: consuming very little, these cells release histamine and are important in some allergic reactions (such as asthma) and also defending against parasites. They are mobilized by the antibody type IgE.
• Eosinophil granulocyte: a non-consuming cell related to the neutrophil. An important part of defense against parasites.

Neutrophils, eosinophils and basophils are also known as polymorphonuclear leukocytes (due to their lobed nuclei) or granulocytes.

Complement System

The complement system is a biochemical cascade of the immune system that helps clear pathogens from an organism. It is derived from many small plasma proteins working together to form the primary end result of cytolysis by disrupting the target cell's plasma membrane. The proteins are sythesized in the liver, mainly by hepatocytes.

Other non-specific proteins include Protease C3-convertase, which is also sythesized in the liver and connects to other molecules that are commonly found in bacteria but non-existant in humans, stimulating the complement system and phagocytosis.

Inflammatory Response

The inflammatory response is fundamentally a non-specific reaction, despite in practice controlled by specific mechanisms (lymphocytes). It is characterized by the following quintet, defined in Greco-Roman antiquity: redness (rubor), heat (calor), swelling (tumor), pain (dolor) and dysfunction of the organs involved (functio laesa).

Inflammation is stimulated by factors released by injured cells. These factors (histamine, bradicine) sensitize pain receptors and cause dilation of the blood vessels at the scene (rubor and tumor), and also attract phagocytes, especially neutrophils. Phagocytosis causes the neutrophils to release other factors that call lymphocytes and other phagocytes.

Specific or Adaptive Immune System

The basis of specific immunity lies in the capacity of immune cells to distinguish between proteins produced by the body's own cells ("self" antigen - those of the original organism), and proteins produced by invaders or cells under control of a virus ("non-self" antigen - or, what is not recognized as the original organism). This distinction is made via T-Cell Receptors (TCR) or B-Cell Receptors (BCR). For these receptors to be efficient they must be produced in thousands of configurations, this way they are able to distinguish between many different invader proteins. This immense diversity of receptors would not fit in the genome of a cell, and millions of genes, one for each type of possible receptor, would be impractical. What happens is that there are a few families of genes, each one having a slightly different modification. Through a special process, unique to human cells, the genes in these lymphocytes recombine, one from each family, arbitrarily into a single gene.

This way, for example, each antibody or BCR of B lymphocytes has six portions, and is created from two genes unique to this lymphocyte, created by the recomniation (union) of a random gene from each family. If there are 6 families, with 50, 30, 9, 40, and 5 members, the total possible number of antibodies is 50x30x6x9x40x5 = 16 million. On top of this there are other complex processes that increase the diversity of BCR or TCR even more, by mutation of the genes in question. The variability of antibodies is practically limitless, and the immune system creates antibodies for any molecule, even artificial molecules that do not exist in nature.

Many TCR and BCR created this way will react with their own peptides. One of the functions of the thymus and bone marrow is to hold young lymphocytes until it is possible to determine which ones react to molecules of the organism itself. This is done by specialized cells in these organs that present the young lymphocytes with molecules produced by them (and effectively the body). All the lymphocytes that react to them are destroyed, and only those that show themselves to be indifferent to the body are released into the bloodstream.

The lymphocytes that do not react to the body number in the millions, each with millions of possible configurations of receptors, each with a receptor for different parts of each microbial protein possible. The vast majority of lymphocytes never find a protein that its receptor is specified for, those few that do find one are stimulated to reproduce. Effective cells are generated with the specific receptor and memory cells. These memory cells are quiescent, they have long lives and are capable of identifying this antigen some time later, multiplying themselves quickly and rapidly responding to future infections.

The specific immune system is controlled directed largely by lymphocytes. There are various types of lymphocytes:

B Lymphocytes and Antibody Production

see B cells

CD8+ T Lymphocytes and Cytotoxicity

see Cytotoxic T cells

Phagocytes

Though phagocytes are an innate mechanism, since they respond to any foreign body, they are also the first line decision makers for lymphocytes.

Phagocytes, especially macrophages, respond to cytokines generated by lymphocytes. Monocytes are the precursors to macrophages and they transform into macrophages when stimulated by CD4+ T cytokines. They are also attracted by other cytokines and factors emitted by cells in areas of active infection.

If properly stimulated by cytokines emitted in a localized and controlled manner by CD4+ T lymphocytes, the macrophages release sufficient quantities of enzymes and free radicals to completely destroy a localized area, killing both invaders and human cells.

On top of this, under control of lymphocytes, macrophages are responsible for some specific immunological reactions such as granuloma and abscesses. Granuloma occurs during an invasion of microbacteria and fungi, the most well-known example being tuberculosis. It is a reaction commanded by cytokines fro CD4+ T cells, when there is intracellular infection of the phagocytes themselves. In order to stop the invader from entering the bloodstream and spreading throughout the body in these mobile cells, the CD4+ lymphocytes secrete cytokines that call more macrophages, and make them more resistant to infection. Cytokines also provoke an adaptation in macrophages of epithelial morphology around the area of invasion, with numerous layers of immobilized cells connected by water-resistant links as to close off the invader. The tuberculosis microbacteria cannot propagate and remains stagnant. Today hundereds of millions of healthy people have microbacteria controlled in this form within their lungs (visible in x-rays). Only in those that have severely debilitated immunities do these pathogens escape and cause tuberculosis. The abscess is similar, surrounded by a cyst of pus. It is important to sequester pathogenic bacteria whose toxicity kills phagocytes (forming the pus) and does not permit efficient cleaning.

CD4+ Lymphocytes and Response Supervision

CD4+ Lymphocytes, or helper T cells, are immune response controllers. They "decide" which actions to take during an invasion, promoting or inhibiting all other immune cells via cytokines. HIV, being a virus that directly attacks the CD4+ T cells, causes a collapse of the entire system by attacking the root.

CD4+ lymphocytes are able to decide of there is an invasion due to the fact that each cell contains a randomly created TCR. All phagocytes and some other cells, such as dendrites, after digesting the proteins of an invader retain some of the peptides in a protein membrane, MHC. The TCR of the CD4+ T lymphocytes attach to the MHC II via the peptide and if the connection is effective, liberates cytokines. Almost no CD4+ T lymphocytes contain TCRs that react against self peptides, these were destroyed during the cell development in the thymus. If the levels of these cytokines are sufficiently high, and if other, less known factors exist in the blood, the CD4+ T lymphocytes "decide" that there is an invasion and what sort, beginning the specific immune response. The CD4+ T lymphocytes then produce other cytokines activating other cells for the appropriate response. As with other lymphocytes, stimulated CD4+ T lymphocytes multiply and some serve as memory cells to speed up future responses.

There are essentially two types of CD4+ T helpers, corresponding to two types of responses. The TH1 response is characterized by the production of cytokines such as IL-2, IFN-gamma and TNF-beta. Macrophages are activated, and through cytotoxic mechanisms (T lymphocytes), the infected areas are extensively destroyed. It is efficient in elimination of intracellular pathogens (intracellular viruses and bacteria). In the TH2 response there is a release of IL-4 and IL-5. It is characterized by the production of antibodies from B lymphocytes. It is effective against organisms in the blood, such as extra-cellular bacteria and parasites.

Which response (TH1 or TH2) is produced is important to the progression of the infection. For example, in leprosy, an infection caused by the intracellular Mycobacterium leprae, the TH1 response is extremely effective and the infection is kept to minimum (lepra tuberculoide) ; but if a response TH2 is activated, ineffective against intracellular organisms, common leprosy occurs causing extensive damage and loosening of the skin (lepra lepromatosa).

There is a third type of T lymphocyte, the regulatory T cells (Treg), which limit and suppress the immune reaction against self-antigens, an important mechanism considering the extreme destruction the immune system can cause.

Disorders of the human immune system

The most important function of the human immune system occurs at the cellular level of the blood and tissues. The lymphatic and blood circulation systems are paths for specialized white blood cells to travel around the body. White blood cells include B cells, T cells, natural killer cells, macrophages, and dendritic cells. Each has a different responsibility, but all function together with the primary objective of recognizing, attacking and destroying bacteria, viruses, cancer cells, and all other pathogens. Without this coordinated effort, a person would not be able to survive more than a few days before succumbing to an overwhelming infection. When a pathogen has entered the body, it sets off a chain reaction that starts with the activation of macrophages and natural killer cells that reach the site of infection and destroy as much of the pathogen as possible. While this is happening, it is the job of the dendritic cells to take “snap-shots” of the battle-ground to take to the lymph nodes in order to activate T cells which then activate B cells to produce antibodies against the pathogen.

Many disorders of the human immune system fall into two broad categories that are characterized by:

• Weakened immune response: There are 'congenital' (inborn) and 'acquired' forms of immunodeficiency, characterized by an attenuated response. Chronic granulomatous disease, in which phagocytes have trouble destroying pathogens, is an example of the former, while AIDS ("Acquired Immune Deficiency Syndrome"), an infectious disease caused by HIV that destroys CD4⁺ T cells, is an example of the latter. Immunosuppressive medication intentionally induces an immunodeficiency in order to prevent rejection of transplanted organs.

• Overzealous immune response: On the other end of the scale, an overactive immune system figures in a number of other disorders, particularly autoimmune disorders such as lupus erythematosus, type I diabetes (sometimes called "juvenile onset diabetes"), multiple sclerosis, psoriasis, and rheumatoid arthritis. In these, the immune system fails to properly distinguish between self and non-self, and attacks a part of the patient's own body. Other examples of overzealous immune responses in disease include hypersensitivities, such as allergies and asthma.

Other factors that affect immune response

Many factors can also contribute to the general weakening of the immune system:

• Malnutrition (unbalanced diet / poor eating habits that cause a lack of vitamins, minerals and Polyphenol antioxidants)
• Alcohol abuse
• Drug abuse either intravenous or other. (Appears related to associated factors i.e. poor diet, use of infected/dirty needles, poor exercise, stress/depression)
• Medications (particularly the use of anti-cancer drugs, corticosteroids, and antibiotics);
• Radiation
• Exposure to certain environmental toxins, whether naturally occurring or from pollution. These include:
  • Cigarette smoke
• Stress/Depression - Research shows that psychological stress can greatly increase your susceptibility to colds and other viral diseases, namely through an increase in serum corticosteroid levels
• Age - Ability of the immune system to respond is decreased at early and old age.
• Decreased ability to heal due to disease or medications (i.e. Diabetes, corticosteroids, immune suppressant drugs), causing constant exposure to infectious agents without natural defense (intact skin)
• Inadequate sleep at the Delta brain wave level. According to a sleep study, we need 4 hours of Delta sleep every night
• Lack of exercise as well as excessive exercise resulting in physiological stress
• Long-term weightlessness
• Diseases either infectious or other causing more depression on the immune system like:
  • Cancer, and hematological malignancy (such as leukemia, lymphoma and myeloma) in particular.
  • Diabetes Mellitus
  • Cystic fibrosis
  • Lupus Erythematosus
  • Nephrotic syndrome
  • Viral infections i.e. viral respiratory infections then allowing for bacterial pneumonia to develop.
  • HIV
  • Ulcerative colitis
  • Bulimia (due to malnutrition, stress, depression).
  • Sickle-cell disease.
  • Liver disease / cirrhosis
  • Cushing's syndrome
  • Protects
  • Huntington's Chorea

Pharmacology

Despite high hopes, there are no medications that directly increase the activity of the immune system. Various forms of medication that activate the immune system may cause autoimmune disorders. Adjuvants (often Aluminium Hydroxide) can be used in conjuction with a vaccine to provoke a quicker immunological reaction.

Suppression of the immune system is often used to control autoimmune disorders or inflammation when this causes excessive tissue damage, and to prevent transplant rejection after an organ transplant. Commonly used immunosuppressants include glucocorticoids, azathioprine, methotrexate, ciclosporin, cyclophosphamide and mercaptopurine. In organ transplants, ciclosporin, tacrolimus, mycophenolic acid and various others are used to prevent organ rejection through selective T cell inhibition.

See also

• antigen/antigenic determinant/epitope/hapten/memory cell
• autoimmune disorders
• CD4 receptor/CD8 receptor/perforin/apoptosis/clonal selection
• Immunostimulator
• immunosuppression
• immunosuppressive drug
• immunotherapy
• lymphatic system/lymphocyte
• macrophage
• major histocompatibility complex/class I MHC/class II MHC
• monoclonal antibody/polyclonal antibody

Further reading

• A standard textbook on the immune system is Immunobiology, by Charles Janeway, et al. The paperback of the sixth edition is ISBN 0815341016. NCBI makes the 5th edition available electronically at [1].

External links

• Immune and Lymphatic system presentation
• Immunology