This series of articles comes with an English-Brazilian Portuguese downloadable glossary of terms used in immunology with the English terms explained (in English) and translated into Portuguese. You can download it now. The file size is 160K and the format is RTF (opens in most word processors).
Cells Involved in Immunity
In Part 1 and Part 2 of this series we presented an overview about immunology, its importance and relationship with other areas of the biomedical sciences, and approached topics such as the “self” and “non-self” recognition, innate and acquired immunity, stressing how the immune system operates in an orchestrated way, leading to an effective immune response. We also learned that there are two basic forms of specific immunity: humoral immunity, basically mediated by antibodies, and cell-mediated immunity in which the responding lymphocytes are the T lymphocytes.
The antibodies which mediate the specific humoral immune response are produced by plasma cells. Plasma cells are cells that evolve from activated B lymphocytes which in turn become activated after interaction with antigens. Plasma cells secrete antibodies that eliminate extracellular microorganisms (that usually do not live inside a cell, such as the pneumococci). In cell-mediated immune responses, another set of lymphocytes, the T lymphocytes, activate macrophages to kill intracellular microbes and/or activate some types of T lymphocytes (called cytotoxic T lymphocytes) to destroy infected cells (such as virus-infected cells) as well as cells bearing new antigens on their surfaces (e.g. malignant cells).
Thus, several cell types are involved in the specific immunity and the three major cell types are:
- Antigen presenting cells (APC): cells that process antigens and present them to specific T and/or B cell receptors.
- B cells—lymphocytes that mature in the Bone Marrow.
- T cells—lymphocytes that mature in the Thymus.
T and B lymphocytes are antigen-specific (they present receptors that can react specifically with the antigen that originated their development), whereas APCs do not display specific receptors for the antigens with which they are interacting.
Antigen presenting cells (APCs)—are a group of cells that do not display antigen-specific receptors, and their main function is processing and presenting antigens to T cell receptors. The most important APCs are the macrophages. Macrophages are long-lived phagocytes, strategically located in different tissues (e.g., Langerhans cells in the skin, Kupffer cells in the liver, microglial cells in the brain), where they can encounter the antigens. They play an important role both in antigen presentation and later, in the course of the immune response, as effector cells in cell-mediated immunity.
Other cells such as dendritic cells (found in lymphoid tissues), monocytes (precursors of macrophages found in blood) and B lymphocytes found in the blood and in different lymphoid organs, such as the lymph nodes) may also function as antigen-presenting cells. Although the different APCs can be found in different locations of the organism and present different morphology, all of them are able to perform the following activities :
- ingest macromolecules and microbes;
- internalize these antigens into the APC’s phagosome;
- process (digest) the antigens into peptides;
- export the processed peptides to the APC surface and present the processed peptides to the B and/or T lymphocytes, in a non-specific way; the presentation of the processed antigen to the lymphocytes occurs after an interaction of the peptide with a protein that belongs to an important group of molecules known as the Major Histocompatibility Complex (MHC), the MHC class II molecule (see below—MHC molecules).
B lymphocytes—are cells that carry some classes of antibodies on their surface and are capable of differentiating into plasma cells, which secrete antibodies against a specific antigen. The antibody binds to microorganisms which somehow managed to escape from the innate (non-specific) immune mechanisms. After binding, the antibody activates the complement system and the phagocytic cells (mainly neutrophils, monocytes and macrophages) leading to the destruction of the microorganisms. The formation of an antibody occurs as follows : each B lymphocyte is programmed to make antibodies with only one specificity (i.e. all antibodies of one B cell have the same recognition site) which are placed on the cell surface as receptors. When an antigen enters the body, it encounters an endless number of B lymphocytes all bearing different antibodies with their own individual recognition site. The antigen binds to the B cell bearing an antigen-specific antibody, activates it (with the help of T cells, see below) and causes clonal proliferation and maturation to plasmocytes. The antibodies secreted by the plasma cells present the same specificity to those that reacted with the B cell receptor.
T lymphocytes —Many microorganisms, like viruses, some bacteria and fungi, live inside host cells where it is impossible for the antibodies to reach them. However, most virally infected cells (and some infected by other microorganisms) display the viral antigens on the surface of the infected cell, which in turn can be recognized by the T cells. T lymphocytes, or T cells, mediate cellular immunity, which protects the individual against intracellular microorganisms (some bacteria and fungi species, as well as virus) and tumor cells.
Analogous to B cells, T cells have their own typical antigen receptor called the T cell receptor (TCR). The TCR recognizes a complex present on the surface of APC cells or target cells, consisting of an antigenic peptide in association with a protein that belongs to the MHC group of molecules. Binding of the T cell receptor to this antigen-MHC complex results in a metabolic alteration within the T cell, the sort of which depends on the intracellular compartment in which the pathogen resides.
There are two main T cell subsets: the T helper cells (Th) and the cytotoxic T cells (Tc).
Th cells—are lymphocytes which express on their surface a molecule named CD4; thus in some instances these cells are also referred to as CD4+ T cells. Th cells respond to specific antigenic stimulation (i.e. the binding of antigen to the TCR) by secreting cytokines, such as interleukin-4 (IL-4), interleukin-5 (IL-5), interferon-g, (IFN-g). Some of these cytokines, secreted through the Th activation, stimulate B cells to respond more effectively to antigens, in their antibody production. Other cytokines, such as the IFN-g, secreted by other Th cells stimulate macrophages in their responses to antigens, activating them to kill the microorganism in a more effective way.
Tc cells - are T lymphocytes that express a molecule named CD8 on their surfaces, are effector cells and they act by destroying only those cells whose antigen/peptides are complexed with MHC class I molecules (and expressed in the surface of the infected cell) they can recognize. Tc cells can also recognize and destroy foreign MHC alone, thus being responsible for graft rejections.
The Major Histocompatibility Complex
Class I and class II MHC molecules are encoded by genes and are also responsible for acceptance or rejection of transplanted tissue. The genes of the major histocompatibility complex encode for three different types of proteins: class I, class II and class III, the last of which do not work as antigen presenting molecules but mostly are directly or indirectly related to immune defense functions. Although the term MHC is used for the genetic region at a certain chromosome that encodes for the antigen presenting molecule, sometimes it is applied to the antigen presenting molecule itself
An essential aspect is that the MHC molecules are highly polymorphic and unique to each individual, except for identical twins. This great variability in MHC molecules between individuals is caused by several variable amino acids in the MHC molecule. This phenomenon is based on the fact that the genes of loci encoding for a certain MHC molecule, can have many alternative forms, i.e. many alleles, which explains the distinct allotypes each individual presents, as unique as each person’s fingerprint.
MHC molecules are essential for reactions of immune recognition. Different MHC molecules are recognized by different T cells. Tc cells, involved in recognition and destroying/rejecting virally infected cells and foreign tissue grafts, recognize the complex MHC class I molecules-antigen or the MHC class I alone of foreign cells (grafts). These Tc cells, helped by the Th cells, will then destroy the infected cells and/or the foreign grafts.
It should be noted that Tc cells will kill viral infected cells, if they can see viral antigens complexed with its own MHC class I molecule. If the Tc cell “sees” an antigen in conjunction with a MHC molecule of a different allotype (from a different person), it will not be able to recognize and destruct. Thus antigen recognition by the Tc cells is restricted to MHC class I molecules.
Class I molecules are present on almost all cells of the body. This is an important evolutionary acquisition since virally infected cells may occur in any cell type of our organism.
On the other hand, MHC class II proteins are more restricted than class I molecules and they are only present on cells involved in the immune response, e.g. B cells, APCs and macrophages. This also makes sense since these molecules are involved in the presentation of antigens to Th cells by B cells, APCs and macrophages. These Th cells once activated (after “seeing” the antigen-MHC class II complex) will cooperate with B cells to induce antibody production and they can also release lymphokines, which help macrophages to kill intracellular organisms.
Antibodies
Antibodies, generically referred to as immunoglobulins, are glycoproteins found in the blood and other biological fluids as soluble proteins and as membrane-bound proteins on the surface of cells, especially on B lymphocytes. Each immunoglobulin is essentially bifunctional: it binds specifically to molecules (antigen) from a pathogen/foreign substance that elicited the immune response and recruits other cells and molecules to destroy the pathogen or non-self molecule, to which the antibody is bound.
Each function is accomplished in separate structural regions of the antibody molecule. The region which binds the antigen is the variable region (which displays an aminoacid sequence which varies considerably, according to the antigenic determinant which specifically can “fit” into it) and the part which recruits cells and other molecules is the constant region. Some characteristic variations in the aminoacid sequences of the constant parts (also called domains) of the immunoglobulins distinguish different classes or isotypes of antibodies. The different classes of immunoglobulins have different characteristics and functions.
Once a B cell expressing a specific antibody interacts with an antigen, it will divide many times and some of them will differentiate into plasma cells and produce antibodies, while others will differentiate into long-lived B cells, called memory cells. These memory cells will rapidly expand and secrete high amounts of specific antibody after encountering the same antigen again; this type of response is known as secondary response or anamnestic response. Secondary responses explain why a second encounter with an antigen is much more effective and explains why we become immunized after having some types of infection or when we are vaccinated. In addition, the antibody produced in the secondary anamnestic response is of a different isotype than the antibody produced in the primary response. There are five isotypes of antibody in humans:
IgG
IgM
IgA
IgD
IgE
IgG antibodies account for about 75% of the total serum immunoglobulin in normal adults and are the predominant antibodies produced in the secondary anamnestic response. IgG antibodies are found as soluble immunoglobulins in serum and other biological fluids, and can bind to certain types of cells, such as macrophages, via a receptor specific to the constant region of the IgG molecule. The binding of antigen to IgG so bound to macrophages can induce the cell to phagocyte the antigen/antibody complex.
IgM antibodies account for about 10% of the total serum antibodies and are largely confined to the intravascular spaces. IgM molecules are the first antibodies to appear after a primary immune response. Antibodies of this class are very effective at activating the complement system by a pathway dependent on the antigen-antibody interaction, the so called classical pathway, and in this way, are very effective at clearing bacteria and some fungi from the blood.
IgA is the main immunoglobulin class in secretions, such as the tears, milk, colostrum, and mucosal surfaces. It is also the second most abundant immunoglobulin class in serum but its effectiveness at mucosal surfaces is unique. IgA antibodies do not fix complement, although they are important in the neutralization of some toxins and microorganisms, such as bacterial toxins and viruses.
IgD immunoglobulins are detected in blood at very low concentrations by using very sensitive methods. They are mainly present as membrane-bound immunoglobulins on the surface of mature B cells where they are co-expressed with IgM molecules. At present, the function of IgD is somewhat unclear.
IgE immunoglobulins are found in extremely low concentrations in the blood. However, they are found on the surface membrane of basophils and mast cells. IgE molecules are bound to the mast cells and basophils via special receptors on the surface of these cells, specific for the amino terminal region of IgE molecule. IgE antibody levels in serum are highly increased in patients infected with helminthic diseases, such as Ascaris lumbricoides and so there are indications that this immunoglobulin class plays an important role in the defense against some helminth species.
All of these antibody molecules act co-operatively along with a number of other recognition molecules (the MHC molecules, the TCR, CD4 and CD8 molecules, various cytokines, the complement system and other molecules not mentioned in this brief overview). Also the various cells of the immune system cooperate to bring together the effector cells and/or humoral activities with the microorganism, their toxins, or the host infected cells. The end result is, provided antigen has been recognized and processed appropriately, the killing of the microorganism or the infected cell.
Immunopathology
Until now, the immune system was presented as an wonderful system, capable of quite effectively defending the body against “non-self” molecules and cells, thus preserving our body integrity. However, the immune system can also be the source of many pathological conditions that can arise through deficiencies of the immune system, as well as by excessive activation or aberrant activation of the cells and molecules of the immune system. In these cases, the immune system itself can be the cause of pathological conditions. These pathological conditions include autoimmune diseases, reactions against grafts, hypersensitivities and allergies, some responses to tumours and some immunodeficiency disorders, including AIDS.
Autoimmune diseases arise when our organism produces aberrant T cells or antibodies that are able to react with antigens present in our own cells or tissues.
Autoimmune diseases, mainly those in which autoimmunity contributes to, or has an association with, the pathogenesis of the disease, can be classified into two broad, but overlapping, groups: organ-specific and non-organ-specific (or systemic) autoimmune diseases. In the first type, autoimmunity is directed against one organ. Examples of organ-specific autoimmune diseases include, among others, Hashimoto’s thyroiditis (thyroid gland), pernicious anemia (stomach), Addison’s disease (adrenal glands). In systemic disorders, autoimmunity is widely spread throughout the body. Examples of systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus (SLE or lupus), and dermatomyositis. Some autoimmune diseases fall between these two polar types.
Autoimmune processes can lead to slow destruction of a specific type of cells or tissue, stimulation of an organ into excessive growth, or interference in its function. Organs and tissues frequently affected include the endocrine glands (such as the thyroid, pancreas, and adrenal glands), components of the blood (such as red blood cells), and connective tissues (skin, muscles, and joints).
The disease may be mediated by antibodies, immunecomplexes and/or by T cells. For example, in myasthenia gravis, antibodies directed to the acetylcholine receptor found in neuromuscular junctions, lead to muscle weakness and death. In SLE, immune complexes are formed with DNA-antibodies directed to DNA and complement components; these complexes can deposit on the walls of small blood vessels causing vasculitis in various organs. When these immunecomplexes are deposited in the kidney glomeruli, severe damage to the kidneys may occur. Rheumatoid arthritis is characterized by the presence of Rheumatoid Factors (RF); these RF are IgM antibodies directed against the patient’s own immunoglobulins. In cases of insulin-dependent (juvenile) diabetes mellitus, the presence of cytotoxic T cells specific for surface proteins of the beta cells of the pancreas prevents these cells from producing insulin.
Hypersensitivity reactions occur when the immune response is exaggerated or inappropriate and causes tissue damage. One hypersensitivity reaction type is allergy, which occurs when some usually innocuous substances, such as dust, pollen, drugs, or some foods are recognized as “non-self” and the immune system mounts an inappropriate response to them, giving rise to symptoms of hypersensitivity. Allergy occurs when an IgE response is directed against an innocuous antigen. Upon a second contact with this same antigen, the pre-formed IgE bound to mast cells react with the antigen and this reaction will trigger the release of pharmacological mediators from the mast cells. The release of these pharmacological mediators (e.g. histamine) produces an acute inflammatory reaction. Symptoms of allergy are highly varied, because different allergens stimulate the immune system at different sites in the body. The respiratory tract is the most common site of allergic reactions, with allergens in the upper airways causing sneezing and nasal congestion (rhinitis, hay fever), while allergens in the lower airways cause the bronchoconstriction typically found during asthma episodes. Food allergens cause immune activation in the gastrointestinal tract, leading to nausea, vomiting, abdominal cramps, and diarrhea. Local immune activation in the skin results in contact dermatitis. Anaphylaxis is the most serious form of hypersensitivity reaction and it occurs when an allergen enters the circulation and causes allergic manifestations at sites distant from the site of entry. In severe anaphylaxis, the normal body functions are disrupted to the point that the patient may die.
Hypersensitivity can also occur during infections. In some instances the amount of damage produced by the immune response to a resistant microorganism may be even worse than that produced by the infection itself.
In addition to autoimmune diseases and hypersensitivity reactions, rejection of transplants is another condition caused by detrimental effects of the immune response. As mentioned above, MHC proteins are powerful tools for our organism to recognize antigens in our own cells’ context, and to mount an immune response toward foreign substances. These same molecules, however, can elicit the powerful responses that are responsible for the rejection of grafts and organ transplants from one individual to another. A graft is permanently accepted only when most of the histocompatibility antigens are present in the recipient of the graft. If the recipient lacks the transplantation antigens, he/she will mount immune responses to those antigens and the resulting reactions will lead to the destruction or rejection of the graft.
Graft rejections are primarily mediated by cytotoxic T cells, inflammatory Th cells, or both.
We could see that aberrant or exaggerated immune responses can be detrimental and even fatal. Similarly, the immunodeficiencies are usually severe diseases and some of them are fatal. Some of the severe deficiencies of the immune system are inheritable. Others are congenital or acquired later in life. Acquired immunodeficiencies are sometimes a consequence of the destruction of the blood cells by drugs and radiation used to treat cancer. However, the most common acquired immunodeficiency in the last two decades has been AIDS, which is associated with infection by the HIV (human immunodeficiency virus).
Recurrent infections are the most conspicuous symptoms of immunodeficiencies. Besides AIDS, other immunodeficiencies—genetic, congenital or acquired—may occur and they can be ascribed to antibody, complement, APCs or T cells deficiencies. Some examples of immunodeficiencies include X-linked agammaglobulinemia, severe combined immunodeficiency syndrome, common variable immunodeficiency, and other diseases.
X-linked agammaglobulinemia is a genetic disease linked to the X chromosome and is seen in very young children. The patients do not have plasma cells and cannot form any type of antibody after infection or immunization. However, the T cell compartment remains intact and these children can therefore recover from some viral diseases, in which the T cells present the most prominent role.
Severe combined immunodeficiency disease (SCID) is also an inherited disease, characterized by recurrent infections that appear a few months after birth. There are different types of SCID: some are inherited as an X-linked disorder while others are inherited in an autosomal recessive way. Infections with common virus (such as varicella, herpes) as well as atempts to inject live vaccines, may lead to death. This is a typical T cell deficiency: the number of circulating T cells is low and sometimes serum immunoglobulin levels are low.
Common variable immunodeficiency is characterized by unusual infections and low levels of serum immunoglobulins, antibodies. The cause of the disease is not well known, although it is already clear that it is not induced by a single defect since B lymphocytes may be either absent or reduced, helper T lymphocytes may be deficient or another set of T lymphocytes (not discussed herein), the suppressor T lymphocytes, may be excessive. Unlike X-linked agammaglobulinemia, common variable immunodeficiency is not inherited in a single, well-defined pattern. This condition is a relatively common form of immunodeficiency, and the particular antibody deficiency (IgG alone, both IgG and IgA, or IgG, IgA and IgM together) can vary from patient to patient. Not only does the disorder range from severe to mild, but it can also occur at any age.
Final Note
This article and the previous ones published in this series are intended to provide very basic information about immunology to my translator colleagues, in such a way that they can understand some concepts, as well as some expressions and words used by immunologists. I hope these articles and the accompanying glossary will help other translators, when they face texts on immunology and related sciences.
If you have any questions, comments or suggestions for further topics in the field of immunology or immunology nomenclature, please contact the author at: lsinger@icb.usp.br or at Lsinger@originet.com.br.
Once more I want to express my gratitude to my old friend Gabe Bokor for the opportunity to publish this series and accompanying glossary in the Translation Journal.
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