The skin, respiratory passages, intestinal tract and other areas are protected from foreign antigens by a collection of cells and proteins, which is called the immune system. When a pathogen intrudes the innate immunity is the first defence, that happens immediately or within hours of encountering the antigen. Its defence mechanism is antigen-independent and has no memory, so it is unable to react quickly when the same antigen intrudes again. Adaptive immunity, however, is antigen-dependent and specific. Therefore there is some time between the exposure to the antigen and its maximal response. Because of the memory capacity adaptive immunity reacts quickly upon subsequent exposure to the antigen. Innate and adaptive immunity complement each other. However, when there are defects in either system the host is vulnerable.

What is meant by innate immunity?

The innate immunity recruits immune cells when there is an infection or inflammation, by producing cytokines. By release of cytokines, antibodies and other proteins and glycoproteins are released. These activate a cascade to identify and opsonize foreign antigens, through which they become vulnerable to phagocytosis. Another function of the innate immunity is to remove dead cells and antibodies and foreign substances in the organs, tissues, blood and lymph. The adaptive immune response is activated by the presentation of the antigen.

There are many cells involved in the innate immune responses. Each of them will be shortly described below. Phagocytes have two types, namely neutrophils and macrophages. Both engulf the microbes, though there mechanisms somewhat differ. Neutrophils contain granules that, upon release, help in removing the pathogenic microbes. Macrophages live long and present antigens to T cells. Another part of the innate immune response is fulfilled by dendritic cells. They phagocytose and are antigen-presenting cells (APCs). They are also messengers between the innate and adaptive immunity.

Mast cells and basophils share many features, such as that they initiate the acute inflammatory responses, like in allergy and asthma. Mast cells can be found in connective tissue surrounding the blood vessels, while basophils are in the circulation. Eosinophils are granulocytes with phagocytic features. They demolish parasites, too large for phagocytosis. They are also important in the control mechanisms of allergy and asthma. Natural killer cells reject tumours and demolish cells infected by viruses, by releasing perforins and granzymes that induce apoptosis. There are four types of defences in the innate immunity (see table 1, p. 89 of the reader): anatomic, physiologic, endocytic and phagocytic, and inflammatory.

What is meant by adaptive immunity?

When infectious agents haven’t been removed by innate immunity, the adaptive immunity becomes active. It recognizes ‘non-self’ antigens in the presence of ‘self’ antigens; generates pathogen-specific immunologic effector pathways to eliminate pathogens or pathogen-infected cells; and develop a memory to quickly respond to a specific pathogen. There are two types of cells, namely T and B cells.

T cells reside in the hematopoietic stem cells in the bone marrow, but mature in the thymus. The T-cell receptor is unique to antigens. There activation requires action from APCs to recognize the specific antigen. On the surface of the APCs are major histocompatibility complexes (MHC). Class I MHC is found on all nucleated cells and present endogenous peptides. Class II MHC is present in macrophages, dendritic cells and B cells and present exogenous peptides. When a cell is infected with a pathogen or has phagocytosed foreign proteins, the MHC protein displays fragments of antigens, which are recognised by T cells. T cells secrete cytokines and they differentiate into either cytotoxic T cells or T-helper (Th) cells.

Cytotoxic T cells destroy cells that are infected by foreign agents. They are activated by interaction of their TCR with MHC class I molecules. Cytotoxic T cells multiply and release perforin, granzyme and granulysin. The effector cells are removed by phagocytes when the infection is removed. However, few of them remain as memory cells to be able to quickly respond upon subsequent encounters with the antigen. Th cells establish and maximise the immune response. When their TCR recognises the antigen of class II MHC molecules, the Th cells are activated. By releasing cytokines they influence the tasks of the other cells in the immune response.

There are two types of Th cells: Th1 and Th2. Bactericidal activities of macrophages and other cytokines are activated by the production of interferon-gamma in the Th1 response. It also leads to the production of opsonising and neutralising antibodies in B cells. With the Th2 response cytokines are secreted to activate and/or recruit immunoglobulin E (IgE) antibody-producing B cells, mast cells and eosinophils. The IgE antibodies are associated with allergic reactions, so when there is an imbalance of the TH2 cytokine production this can lead to atopic conditions. Th cells die when the infection is effectively combatted, with a few remaining as memory cells. Regulatory T cells limit and suppress the immune system to control aberrant immune responses to self-antigens and the development of auto-immune disease.

B cells arrive from hemotopoietic stem cells in the bone marrow, but after maturation leave and present a unique antigen-binding receptor. They don’t APCs to be activated. B cells are activated by foreign antigens, upon which they proliferate and form into antibody-secreting plasma cells or memory B cells. The memory cells make sure that the body can respond quickly to remove a foreign antigen. Plasma cells are short-lived and don’t express antigen-binding receptors. They die when the foreign agent is eliminated.

How is antibody-mediated immunity initiated?

Antibody-mediated immunity is initiated by B cells. The B cell recognises an antigen and binds to it. Upon this, Th cells release cytokines, by which B cells multiply and form antibody-secreting plasma cells. The antibodies bind to the antigens, so the body knowns they have to be destroyed. When the pathogen is removed, antigen-antibody complexes are cleared. There are five types of antibodies produced by C cells: immunoglobulin A (IgA), IgD, IgE, IgG and IgM, each with different functions and recognising different pathogens (see table 2, p. 91 of the reader).

What mechanisms are there for cell-mediated immunity?

Cell-mediated immunity is the most important defence. There are several mechanisms:

• activating cytotoxic T cells to induce apoptosis of cells displaying foreign antigens;

• activating macrophages and NK cells to destroy intracellular pathogens;

• stimulate cytokine production.

When microbes survive phagocytosis or there are infected non-phagocytic cells, the cell-mediated immunity starts. Virus-infected cells are eliminated by this type of immunity, just as fungi, protozoa, cancers and intracellular bacteria. It also plays a role in transplant rejection.

Immunisation

Passive immunisation is the transfer of active humoral immunity, which are antibodies, from one individual to another. This can be naturally through transplacental transfer to the foetus, or artificially by injection of exogenous antibodies. Injection is used when the risk of infection is high and the body doesn’t have enough time to develop its own immune response, or to reduce symptoms of chronic or immunosuppressive diseases. Active immunisation is the production of antibodies upon exposure to a specific agent. This is done with natural infections with a microbe or with a vaccine with attenuated pathogens or inactivated organisms.

What diseases act upon defects in immune responses?

A disease can occur through an overactive immune response, through an inappropriate reaction to self or through ineffective immune responses.

Hypersensitivity

When the normal immune system has an undesirable response this can lead to hypersensitivity reactions. There are four types:

• type I: immediate hypersensitivity;

• type II: cytotoxic or antibody-dependent hypersensitivity;

• type II: immune complex disease;

• type IV: delayed-type hypersensitivity.

Type I occurs most often and is an allergic reaction by re-exposure to a specific type of antigen, namely an allergen. IgE is secreted by plasma cells, which binds to receptors of mast cells and blood basophils, through which they become ‘sensitised’. When the body is later exposed to the same allergen, this results in degranulation and secretion of active mediators, leading to vasodilatation and smooth-muscle contraction of surrounding tissue. This can be caused by environmental allergens or food allergens for instance. Treatment is to avoid the trigger, to pharmacologically intervene with bronchodilators, antihistamines and anti-inflammatory agents or to induce immunotherapy.

Type II is rare and develops 2 to 24 hours after exposure. It occurs when IgG and IgM antibodies bind to own cell-surface molecules, which activates the complement system. The result is opsonisation, red blood cell agglutination, cell lysis and death. Type III occurs when IgG and IgM antibodies bind to soluble proteins. This forms immune complexes that deposit in tissues, resulting in complement activation, inflammation, neutrophil influx and mast cell degranulation. It takes hours, days or weeks to develop. It can be treated by anti-inflammatory agents and corticosteroids. Type IV reactions take two or more days to develop. They are cell-mediated and antibody-independent and cuased by overstimulation of T cells and monocytes/macrophages. It leads to the secretion of cytokines to cause inflammation, cell death and tissue damage. By avoiding the triggers and use topical corticosteroids, it is easily treatable.

Autoimmunity and immunodeficiency

Autoimmunity is the loss of normal immune homeostasis to produce an abnormal response to own tissue. In this case self-reactive T cells are present, just as auto-antibodies and inflammation. When the ability to fight infectious diseases is compromised or absent, you call this immunodeficiency. It can be caused by a congenital defect or acquired by for instance viral or bacterial infections, malnutrition or treatment with drugs. Diseases, such as leukemia and multiple myeloma, can also impair the immune system. The human immunodeficiency virus (HIV) infects Th cells and impairs other immune system responses, thereby leading to acquired immunodeficiency syndrome (AIDS).