A biological system is a complex network
of biologically relevant entities. Biological organization spans
several scales and are determined based different structures depending
on what the system is. Examples of biological systems at the macro scale are populations of organisms. On the organ and tissue scale in mammals and other animals, examples include the circulatory system, the respiratory system, and the nervous system. On the micro to the nanoscopic scale, examples of biological systems are cells, organelles, macromolecular complexes and regulatory pathways. A biological system is not to be confused with a living system, such as a living organism.
Lymphatic system: structures involved in the transfer of lymph between tissues and the blood stream; includes the lymph and the nodes and vessels. The lymphatic system includes functions including immune responses and development of antibodies.
Immune system: protects the organism from foreign bodies.
The notion of system (or apparatus) relies upon the concept of vital or organic function: a system is a set of organs with a definite function. This idea was already present in Antiquity (Galen, Aristotle), but the application of the term "system" is more recent. For example, the nervous system was named by Monro (1783), but Rufus of Ephesus
(c. 90-120), clearly viewed for the first time the brain, spinal cord,
and craniospinal nerves as an anatomical unit, although he wrote little
about its function, nor gave a name to this unit.
The enumeration of the principal functions - and consequently of
the systems - remained almost the same since Antiquity, but the
classification of them has been very various, e.g., compare Aristotle, Bichat, Cuvier.
The notion of physiological division of labor, introduced in the 1820s by the French physiologist Henri Milne-Edwards, allowed to "compare and study living things as if they were machines created by the industry of man." Inspired in the work of Adam Smith,
Milne-Edwards wrote that the "body of all living beings, whether animal
or plant, resembles a factory ... where the organs, comparable to
workers, work incessantly to produce the phenomena that constitute the
life of the individual." In more differentiated organisms, the
functional labor could be apportioned between different instruments or
systems (called by him as appareils).
Cellular Organelle Systems
The exact components of a cell are determined by whether the cell is a eukaryote or prokaryote.
Nucleus: storage of genetic material; control center of the cell.
Cytosol: component of the cytoplasm consisting of jelly-like fluid in which organelles are suspended within
Endoplasmic reticulum: outer part of the nuclear envelope
forming a continuous channel used for transportation; consists of the
rough endoplasmic reticulum and the smooth endoplasmic reticulum
Rough endoplasmic reticulum (RER): considered "rough" due to the ribosomes attached to the channeling; made up of cisternae that allow for protein production
Smooth endoplasmic reticulum (SER): storage and synthesis of lipids and steroid hormones as well as detoxification
Ribosome: site of biological protein synthesis essential for internal activity and cannot be reproduced in other organs
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells.
For example, the epitope is the specific piece of the antigen to which
an antibody binds. The part of an antibody that binds to the epitope is
called a paratope. Although epitopes are usually non-self proteins, sequences derived from the host that can be recognized (as in the case of autoimmune diseases) are also epitopes.
The epitopes of protein antigens are divided into two categories, conformational epitopes and linear epitopes, based on their structure and interaction with the paratope.
Conformational and linear epitopes interact with the paratope based
on the 3-D conformation adopted by the epitope, which is determined by
the surface features of the involved epitope residues and the shape or tertiary structure
of other segments of the antigen. A conformational epitope is formed
by the 3-D conformation adopted by the interaction of discontiguous
amino acid residues. In contrast, a linear epitope is formed by the 3-D
conformation adopted by the interaction of contiguous amino acid
residues. A linear epitope is not determined solely by the primary structure
of the involved amino acids. Residues that flank such amino acid
residues, as well as more distant amino acid residues of the antigen
affect the ability of the primary structure residues to adopt the epitope's 3-D conformation. The proportion of epitopes that are conformational is unknown.
Function
T cell epitopes
T cell epitopes are presented on the surface of an antigen-presenting cell, where they are bound to MHC
molecules. In humans, professional antigen-presenting cells are
specialized to present MHC class II peptides, whereas most nucleated somatic cells
present MHC class I peptides. T cell epitopes presented by MHC class I
molecules are typically peptides between 8 and 11 amino acids in length,
whereas MHC class II molecules present longer peptides, 13-17 amino
acids in length, and non-classical MHC molecules also present non-peptidic epitopes such as glycolipids.
Cross-activity
Epitopes
are sometimes cross-reactive. This property is exploited by the immune
system in regulation by anti-idiotypic antibodies (originally proposed
by Nobel laureate Niels Kaj Jerne).
If an antibody binds to an antigen's epitope, the paratope could become
the epitope for another antibody that will then bind to it. If this
second antibody is of IgM class, its binding can upregulate the immune
response; if the second antibody is of IgG class, its binding can
downregulate the immune response.
Epitope mapping
Epitopes can be mapped using protein microarrays, and with the ELISpot or ELISA techniques. Another technique involves high-throughput mutagenesis, an epitope mapping strategy developed to improve rapid mapping of conformational epitopes on structurally complex proteins.
MHC class I and II epitopes can be reliably predicted by computational means alone, although not all in-silico T cell epitope prediction algorithms are equivalent in their accuracy.
Epitope tags
Epitopes are often used in proteomics and the study of other gene products. Using recombinant DNA techniques genetic sequences coding for epitopes that are recognized by common antibodies can be fused to the gene. Following synthesis,
the resulting epitope tag allows the antibody to find the protein or
other gene product enabling lab techniques for localisation,
purification, and further molecular characterization. Common epitopes
used for this purpose are Myc-tag, HA-tag, FLAG-tag, GST-tag, 6xHis, V5-tag and OLLAS. Peptides can also be bound by proteins that form covalent bonds to the peptide, allowing irreversible immobilisation These strategies have also been successfully applied to the develohttps://en.wikipedia.org/wiki/Epitopepment of "epitope-focused" vaccine design.
Neoantigenic determinant
A neoantigenic determinant is an epitope on a neoantigen, which is a newly formed antigen that has not been previously recognized by the immune system. Neoantigens are often associated with tumor antigens and are found in oncogenic cells.
Neoantigens and, by extension, neoantigenic determinants can be formed
when a protein undergoes further modification within a biochemical
pathway such as glycosylation, phosphorylation or proteolysis.
This, by altering the structure of the protein, can produce new
epitopes that are called neoantigenic determinants as they give rise to
new antigenic determinants. Recognition requires separate, specific antibodies.
In immunology, an antigen (Ag) is a molecule or molecular structure, such as may be present at the outside of a pathogen, that can be bound to by an antigen-specific antibody (Ab) or B cell antigen receptor (BCR). The presence of antigens in the body normally triggers an immune response.
The term "antigen" originally described a structural molecule that
binds specifically to an antibody only in the form of native antigen. It was expanded later to refer to any molecule or a linear molecular fragment after processing the native antigen that can be recognized by T-cell receptor (TCR). BCR and TCR are both highly variable antigen receptors diversified by somatic V(D)J recombination. Both T cells and B cells are cellular components of adaptive immunity.[1] The Ag abbreviation stands for an antibody generator.
Antigens are "targeted" by antibodies. Each antibody is specifically produced by the immune system to match an antigen after cells in the immune system come into contact with it; this allows a precise identification or matching of the antigen and the initiation of a tailored response. The antibody is said to "match" the antigen in the sense that it can bind to it due to an adaptation in a region of the antibody;
because of this, many different antibodies are produced, each able to
bind a different antigen while sharing the same basic structure. In most
cases, an adapted antibody can only react to and bind one specific
antigen; in some instances, however, antibodies may cross-react and bind more than one antigen.
Also, an antigen is a molecule that binds to Ag-specific receptors, but cannot necessarily induce an immune response in the body by itself. Antigens are usually proteins, peptides (amino acid chains) and polysaccharides (chains of monosaccharides/simple sugars) but lipids and nucleic acids become antigens only when combined with proteins and polysaccharides. In general, saccharides and lipids (as opposed to peptides) qualify as antigens but not as immunogens
since they cannot elicit an immune response on their own. Furthermore,
for a peptide to induce an immune response (activation of T-cells by antigen-presenting cells) it must be a large enough size, since peptides too small will also not elicit an immune response.
The antigen may originate from within the body ("self-antigen")
or from the external environment ("non-self"). The immune system is
supposed to identify and attack "non-self" invaders from the outside
world or modified/harmful substances present in the body and usually
does not react to self-antigens under normal homeostatic conditions due to negative selection of T cells in the thymus.
Vaccines
are examples of antigens in an immunogenic form, which are
intentionally administered to a recipient to induce the memory function
of adaptive immune system toward the antigens of the pathogen invading that recipient.
Etymology
Paul Ehrlich coined the term antibody (in German Antikörper) in his side-chain theory at the end of the 19th century.[6] In 1899, Ladislas Deutsch (Laszlo Detre)
(1874–1939) named the hypothetical substances halfway between bacterial
constituents and antibodies "substances immunogenes ou antigenes"
(antigenic or immunogenic substances). He originally believed those
substances to be precursors of antibodies, just as zymogen
is a precursor of an enzyme. But, by 1903, he understood that an
antigen induces the production of immune bodies (antibodies) and wrote
that the word antigen is a contraction of antisomatogen (Immunkörperbildner). The Oxford English Dictionary indicates that the logical construction should be "anti(body)-gen".
Terminology
Epitope – The distinct surface features of an antigen, its antigenic determinant.
Antigenic molecules, normally "large" biological polymers, usually
present surface features that can act as points of interaction for
specific antibodies. Any such feature constitutes an epitope. Most
antigens have the potential to be bound by multiple antibodies, each of
which is specific to one of the antigen's epitopes. Using the "lock and
key" metaphor, the antigen can be seen as a string of keys (epitopes)
each of which matches a different lock (antibody). Different antibody idiotypes, each have distinctly formed complementarity-determining regions.
Allergen – A substance capable of causing an allergic reaction. The (detrimental) reaction may result after exposure via ingestion, inhalation, injection, or contact with skin.
Superantigen – A class of antigens that cause non-specific activation of T-cells, resulting in polyclonal T-cell activation and massive cytokine release.
Tolerogen – A substance that invokes a specific immune non-responsiveness due to its molecular form. If its molecular form is changed, a tolerogen can become an immunogen.
Immunoglobulin-binding protein – Proteins such as protein A, protein G, and protein L
that are capable of binding to antibodies at positions outside of the
antigen-binding site. While antigens are the "target" of antibodies,
immunoglobulin-binding proteins "attack" antibodies.
T-dependent antigen – Antigens that require the assistance of T cells to induce the formation of specific antibodies.
T-independent antigen – Antigens that stimulate B cells directly.
Immunodominant antigens – Antigens that dominate (over all others from a pathogen)
in their ability to produce an immune response. T cell responses
typically are directed against a relatively few immunodominant epitopes,
although in some cases (e.g., infection with the malaria pathogen Plasmodium spp.) it is dispersed over a relatively large number of parasite antigens.
Antigen-presenting cells present antigens in the form of peptides on histocompatibility molecules.
The T cell selectively recognize the antigens; depending on the
antigen and the type of the histocompatibility molecule, different types
of T cells will be activated. For T Cell Receptor (TCR) recognition,
the peptide must be processed into small fragments inside the cell and
presented by a major histocompatibility complex (MHC). The antigen cannot elicit the immune response without the help of an immunologic adjuvant. Similarly, the adjuvant component of vaccines plays an essential role in the activation of the innate immune system.
An immunogen is an antigen substance (or adduct) that is able to trigger a humoral (innate) or cell-mediated immune response.
It first initiates an innate immune response, which then causes the
activation of the adaptive immune response. An antigen binds the highly
variable immunoreceptor products (B cell receptor or T cell receptor)
once these have been generated. Immunogens are those antigens, termed immunogenic, capable of inducing an immune response.
At the molecular level, an antigen can be characterized by its ability to bind to an antibody's variable Fab region. Different antibodies have the potential to discriminate among specific epitopes present on the antigen surface. A hapten
is a small molecule that changes the structure of an antigenic epitope.
In order to induce an immune response, it needs to be attached to a
large carrier molecule such as a protein (a complex of peptides). Antigens are usually carried by proteins and polysaccharides, and less frequently, lipids. This includes parts (coats, capsules, cell walls, flagella, fimbriae, and toxins) of bacteria, viruses, and other microorganisms. Lipids and nucleic acids are antigenic only when combined with proteins and polysaccharides.
Non-microbial non-self antigens can include pollen, egg white, and
proteins from transplanted tissues and organs or on the surface of
transfused blood cells.
Sources
Antigens can be classified according to their source.
Exogenous antigens
Exogenous antigens are antigens that have entered the body from the outside, for example, by inhalation, ingestion or injection. The immune system's response to exogenous antigens is often subclinical. By endocytosis or phagocytosis, exogenous antigens are taken into the antigen-presenting cells (APCs) and processed into fragments. APCs then present the fragments to T helper cells (CD4+) by the use of class II histocompatibility
molecules on their surface. Some T cells are specific for the
peptide:MHC complex. They become activated and start to secrete
cytokines, substances that activate cytotoxic T lymphocytes (CTL), antibody-secreting B cells, macrophages and other particles.
Some antigens start out as exogenous and later become endogenous
(for example, intracellular viruses). Intracellular antigens can be
returned to circulation upon the destruction of the infected cell.
Endogenous antigens
Endogenous antigens are generated within normal cells as a result of normal cell metabolism, or because of viral or intracellular bacterial infection. The fragments are then presented on the cell surface in the complex with MHC class I molecules. If activated cytotoxic CD8+ T cells recognize them, the T cells secrete various toxins that cause the lysis or apoptosis
of the infected cell. In order to keep the cytotoxic cells from killing
cells just for presenting self-proteins, the cytotoxic cells
(self-reactive T cells) are deleted as a result of tolerance (negative selection). Endogenous antigens include xenogenic (heterologous), autologous and idiotypic or allogenic (homologous) antigens. Sometimes antigens are part of the host itself in an autoimmune disease.
Autoantigens
An autoantigen
is usually a normal protein or protein complex (and sometimes DNA or
RNA) that is recognized by the immune system of patients suffering from a
specific autoimmune disease.
Under normal conditions, these antigens should not be the target of the
immune system, but in autoimmune diseases, their associated T cells are
not deleted and instead attack.
Neoantigens
Neoantigens
are those that are entirely absent from the normal human genome. As
compared with nonmutated self-antigens, neoantigens are of relevance to
tumor control, as the quality of the T cell pool that is available for
these antigens is not affected by central T cell tolerance. Technology
to systematically analyze T cell reactivity against neoantigens became
available only recently.[15]
Neoantigens can be directly detected and quantified through a method
called MANA-SRM developed by a molecular diagnostics company, Complete
Omics Inc., through collaborating with a team in Johns Hopkins
University School of Medicine.
Viral antigens
For virus-associated tumors, such as cervical cancer and a subset of head and neck cancers, epitopes derived from viral open reading frames contribute to the pool of neoantigens.
Tumor antigens can appear on the surface of the tumor in the form
of, for example, a mutated receptor, in which case they are recognized
by B cells.
For human tumors without a viral etiology, novel peptides (neo-epitopes) are created by tumor-specific DNA alterations.
Process
A large
fraction of human tumor mutations is effectively patient-specific.
Therefore, neoantigens may also be based on individual tumor genomes.
Deep-sequencing technologies can identify mutations within the
protein-coding part of the genome (the exome)
and predict potential neoantigens. In mice models, for all novel
protein sequences, potential MHC-binding peptides were predicted. The
resulting set of potential neoantigens was used to assess T cell
reactivity. Exome–based analyses were exploited in a clinical setting,
to assess reactivity in patients treated by either tumor-infiltrating lymphocyte
(TIL) cell therapy or checkpoint blockade. Neoantigen identification
was successful for multiple experimental model systems and human
malignancies.
The false-negative rate of cancer exome sequencing is low—i.e.:
the majority of neoantigens occur within exonic sequence with sufficient
coverage. However, the vast majority of mutations within expressed
genes do not produce neoantigens that are recognized by autologous T
cells.
As of 2015 mass spectrometry resolution is insufficient to
exclude many false positives from the pool of peptides that may be
presented by MHC molecules. Instead, algorithms are used to identify the
most likely candidates. These algorithms consider factors such as the
likelihood of proteasomal processing, transport into the endoplasmic reticulum, affinity for the relevant MHC class I alleles and gene expression or protein translation levels.
The majority of human neoantigens identified in unbiased screens
display a high predicted MHC binding affinity. Minor histocompatibility
antigens, a conceptually similar antigen class are also correctly
identified by MHC binding algorithms. Another potential filter examines
whether the mutation is expected to improve MHC binding. The nature of
the central TCR-exposed residues of MHC-bound peptides is associated
with peptide immunogenicity.
Nativity
A native antigen is an antigen that is not yet processed by an APC to smaller parts. T cells cannot bind native antigens, but require that they be processed by APCs, whereas B cells can be activated by native ones.
Antigenic specificity
Antigenic
specificity is the ability of the host cells to recognize an antigen
specifically as a unique molecular entity and distinguish it from
another with exquisite precision. Antigen specificity is due primarily
to the side-chain conformations of the antigen. It is measurable and
need not be linear or of a rate-limited step or equation.
Basic B cell function: bind to an antigen, receive help from a cognate helper T cell, and differentiate into a plasma cell that secretes large amounts of antibodies
Early B cell development: from stem cell to immature B cell
B cells undergo two types of selection while developing in the bone
marrow to ensure proper development, both involving B cell receptors
(BCR) on the surface of the cell. Positive selection occurs through
antigen-independent signaling involving both the pre-BCR and the BCR. If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop.
Negative selection occurs through the binding of self-antigen with the
BCR; If the BCR can bind strongly to self-antigen, then the B cell
undergoes one of four fates: clonal deletion, receptor editing, anergy, or ignorance (B cell ignores signal and continues development). This negative selection process leads to a state of central tolerance, in which the mature B cells don't bind with self antigens present in the bone marrow.
To complete development, immature B cells migrate from the bone marrow into the spleen as transitional B cells, passing through two transitional stages: T1 and T2. Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells. Within the spleen, T1 B cells transition to T2 B cells.
T2 B cells differentiate into either follicular (FO) B cells or
marginal zone (MZ) B cells depending on signals received through the BCR
and other receptors. Once differentiated, they are now considered mature B cells, or naive B cells.
Transitional B cell development: from immature B cell to MZ B cell or mature (FO) B cell
Activation
B cell activation: from immature B cell to plasma cell or memory B cell
B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes.
After B cells mature in the bone marrow, they migrate through the blood
to SLOs, which receive a constant supply of antigen through circulating
lymph. At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR.
Although the events taking place immediately after activation have yet
to be completely determined, it is believed that B cells are activated
in accordance with the kinetic segregation model,
initially determined in T lymphocytes. This model denotes that before
antigen stimulation, receptors diffuse through the membrane coming into
contact with Lck and CD45 in equal frequency, rendering a net
equilibrium of phosphorylation and non-phosphorylation. It is only when
the cell comes in contact with an antigen presenting cell that the
larger CD45 is displaced due to the close distance between the two
membranes. This allows for net phosphorylation of the BCR and the
initiation of the signal transduction pathway.
Of the three B cell subsets, FO B cells preferentially undergo T
cell-dependent activation while MZ B cells and B1 B cells preferentially
undergo T cell-independent activation.
B cell activation is enhanced through the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81 (all three are collectively known as the B cell coreceptor complex).
When a BCR binds an antigen tagged with a fragment of the C3 complement
protein, CD21 binds the C3 fragment, co-ligates with the bound BCR, and
signals are transduced through CD19 and CD81 to lower the activation
threshold of the cell.
T cell-dependent activation
Antigens that activate B cells with the help of T-cell are known as T cell-dependent (TD) antigens and include foreign proteins. They are named as such because they are unable to induce a humoral response in organisms that lack T cells.
B cell responses to these antigens takes multiple days, though
antibodies generated have a higher affinity and are more functionally
versatile than those generated from T cell-independent activation.
Once a BCR binds a TD antigen, the antigen is taken up into the B cell through receptor-mediated endocytosis, degraded, and presented to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane. T helper (TH) cells, typically follicular T helper (TFH) cells recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR). Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21. CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor CD40, which promotes B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as sustains T cell growth and differentiation. T cell-derived cytokines bound by B cell cytokine receptors also promote B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as guide differentiation. After B cells receive these signals, they are considered activated.
T-dependent B cell activation
Once activated, B cells participate in a two-step differentiation
process that yields both short-lived plasmablasts for immediate
protection and long-lived plasma cells and memory B cells for persistent
protection. The first step, known as the extrafollicular response, occurs outside lymphoid follicles but still in the SLO.
During this step activated B cells proliferate, may undergo
immunoglobulin class switching, and differentiate into plasmablasts that
produce early, weak antibodies mostly of class IgM. The second step consists of activated B cells entering a lymphoid follicle and forming a germinal center (GC), which is a specialized microenvironment where B cells undergo extensive proliferation, immunoglobulin class switching, and affinity maturation directed by somatic hypermutation. These processes are facilitated by TFH cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells.
Resultant plasma cells secrete large amounts of antibody and either
stay within the SLO or, more preferentially, migrate to bone marrow.
T cell-independent activation
Antigens that activate B cells without T cell help are known as T cell-independent (TI) antigens and include foreign polysaccharides and unmethylated CpG DNA. They are named as such because they are able to induce a humoral response in organisms that lack T cells.
B cell response to these antigens is rapid, though antibodies generated
tend to have lower affinity and are less functionally versatile than
those generated from T cell-dependent activation.
As with TD antigens, B cells activated by TI antigens need
additional signals to complete activation, but instead of receiving them
from T cells, they are provided either by recognition and binding of a
common microbial constituent to toll-like receptors (TLRs) or by extensive crosslinking of BCRs to repeated epitopes on a bacterial cell.
B cells activated by TI antigens go on to proliferate outside lymphoid
follicles but still in SLOs (GCs do not form), possibly undergo
immunoglobulin class switching, and differentiate into short-lived
plasmablasts that produce early, weak antibodies mostly of class IgM,
but also some populations of long-lived plasma cells.
Memory B cell activation
Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell.
Some memory B cells can be activated without T cell help, such as
certain virus-specific memory B cells, but others need T cell help.
Upon antigen binding, the memory B cell takes up the antigen through
receptor-mediated endocytosis, degrades it, and presents it to T cells
as peptide pieces in complex with MHC-II molecules on the cell membrane. Memory T helper (TH) cells, typically memory follicular T helper (TFH)
cells, that were derived from T cells activated with the same antigen
recognize and bind these MHC-II-peptide complexes through their TCR. Following TCR-MHC-II-peptide binding and the relay of other signals from the memory TFH
cell, the memory B cell is activated and differentiates either into
plasmablasts and plasma cells via an extrafollicular response or enter a
germinal center reaction where they generate plasma cells and more
memory B cells. It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs.
B cell types
Plasmablast - A short-lived, proliferating antibody-secreting cell arising from B cell differentiation.
Plasmablasts are generated early in an infection and their antibodies
tend to have a weaker affinity towards their target antigen compared to
plasma cell.
Plasmablasts can result from T cell-independent activation of B cells
or the extrafollicular response from T cell-dependent activation of B
cells.
Plasma cell - A long-lived, non-proliferating antibody-secreting cell arising from B cell differentiation. There is evidence that B cells first differentiate into a plasmablast-like cell, then differentiate into a plasma cell.
Plasma cells are generated later in an infection and, compared to
plasmablasts, have antibodies with a higher affinity towards their
target antigen due to affinity maturation in the germinal center (GC)
and produce more antibodies.
Plasma cells typically result from the germinal center reaction from T
cell-dependent activation of B cells, however they can also result from T
cell-independent activation of B cells.
Memory B cell - Dormant B cell arising from B cell differentiation.
Their function is to circulate through the body and initiate a
stronger, more rapid antibody response (known as the anamnestic
secondary antibody response) if they detect the antigen that had
activated their parent B cell (memory B cells and their parent B cells
share the same BCR, thus they detect the same antigen).
Memory B cells can be generated from T cell-dependent activation
through both the extrafollicular response and the germinal center
reaction as well as from T cell-independent activation of B1 cells.
B-2 cell - FO B cells and MZ B cells.
Follicular (FO) B Cell
(also known as a B-2 cell) - Most common type of B cell and, when not
circulating through the blood, is found mainly in the lymphoid follicles
of secondary lymphoid organs (SLOs). They are responsible for generating the majority of high-affinity antibodies during an infection.
Marginal zone (MZ) B cell
- Found mainly in the marginal zone of the spleen and serves as a first
line of defense against blood-borne pathogens, as the marginal zone
receives large amounts of blood from the general circulation.
They can undergo both T cell-independent and T cell-dependent
activation, but preferentially undergo T cell-independent activation.
B-1 cell - Arises from a developmental pathway different from FO B cells and MZ B cells. In mice, they predominantly populate the peritoneal cavity and pleural cavity, generate natural antibodies (antibodies produced without infection), defend against mucosal pathogens, and primarily exhibit T cell-independent activation.
A true homologue of mouse B-1 cells has not been discovered in humans,
though various cell populations similar to B-1 cells have been
described.
Regulatory B (Breg) cell - An immunosuppressive
B cell type that stops the expansion of pathogenic, pro-inflammatory
lymphocytes through the secretion of IL-10, IL-35, and TGF-β. Also, it promotes the generation of regulatory T (Treg) cells by directly interacting with T cells to skew their differentiation towards Tregs.
No common Breg cell identity has been described and many Breg cell
subsets sharing regulatory functions have been found in both mice and
humans.
It is currently unknown if Breg cell subsets are developmentally linked
and how exactly differentiation into a Breg cell occurs.
There is evidence showing that nearly all B cell types can
differentiate into a Breg cell through mechanisms involving inflammatory
signals and BCR recognition.
A study that investigated the methylome of B cells along their differentiation cycle, using whole-genome bisulfite sequencing
(WGBS), showed that there is a hypomethylation from the earliest stages
to the most differentiated stages. The largest methylation difference
is between the stages of germinal center B cells and memory B cells.
Furthermore, this study showed that there is a similarity between B cell
tumors and long-lived B cells in their DNA methylation signatures.
Growth hormone therapy refers to the use of growth hormone (GH) as a prescription medication—it is one form of hormone therapy. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. Growth hormone is now produced by recombinant DNA
technology and is prescribed for a variety of reasons. GH therapy has
been a focus of social and ethical controversies for 50 years.
Growth hormone deficiency is treated by replacing GH. All GH prescribed in North America, Europe, and most of the rest of the world is a human GH, manufactured by recombinant DNA technology.
As GH is a large peptide molecule, it must be injected into
subcutaneous tissue or muscle to get it into the blood. Nearly painless
insulinsyringes make this less trying than is usually anticipated, but perceived discomfort is a subjective value.
When treated with GH, a deficient child will begin to grow faster
within months. Other benefits may be noticed, such as increased
strength, progress in motor development, and reduction of body fat. Side-effects of this type of physiologic replacement are quite rare.
Still, costs of treatment in terms of money, effort, and perhaps quality of life
are substantial. Treatment of children usually involves daily
injections of growth hormone, usually for as long as the child is
growing. Lifelong continuation may be recommended for those most
severely deficient as adults. Most pediatric endocrinologists
monitor growth and adjust dose every 3–4 months. Assessing the
psychological value of treatment is difficult, but most children and
families are enthusiastic once the physical benefits begin to be seen.
Treatment costs vary by country and by size of child, but $US 10,000 to
30,000 a year is common.
Little except the cost of treating severely deficient children is
controversial, and most children with severe growth hormone deficiency
in the developed world are offered treatment, although most accept.
HGH deficiency in adults
The Endocrine Society
has recommended that adult patients diagnosed with growth hormone
deficiency (GHd) be administered an individualized GH treatment regimen.
With respect to diagnosis, their guidelines state that "adults
patients with structural hypothalamic/pituitary disease, surgery or
irradiation in these areas, head trauma, or evidence of other pituitary
hormone deficiencies be considered for evaluation for acquired GHd" and
that "idiopathic GHd in adults is very rare, and stringent criteria are
necessary to make this diagnosis. Because in the absence of suggestive
clinical circumstances there is a significant false-positive error rate
in the response to a single GH stimulation test, we suggest the use of
two tests before making this diagnosis."
GH replacement therapy can provide a number of measurable benefits to GH-deficient adults. These include improved bone density, increased muscle mass, decrease of adipose tissue, faster hair and nail growth, strengthened immune system, increased circulatory system, and improved blood lipid levels, but long term mortality benefit has not yet been demonstrated.
A peer-reviewed article published in 2010 indicates that "Growth
hormone (GH) replacement unequivocally benefits growth, body
composition, cardiovascular risk factors and quality of life. Less is
known about the effects of GH on learning and memory."
Turner syndrome
epitomizes the response of non-deficient shortness. At doses 20% higher
than those used in GH deficiency, growth accelerates. With several
years of treatment the median gain in adult height is about 2–3 in
(5.1–7.6 cm) on this dose. The gains appear to be dose-dependent. It has been used successfully in toddlers with Turner syndrome, as well as in older girls.
Chronic kidney failure results in many problems, including growth failure. GH treatment for several years both before and after transplantation
may prevent further deceleration of growth and may narrow the height
deficit, though even with treatment net adult height loss may be about
4 in (10 cm)
Prader–Willi syndrome,
a generally non-hereditary genetic condition, is a case where GH is
prescribed for benefits in addition to height. GH is one of the
treatment options an experienced endocrinologist may use when treating a
child with PWS. GH can help children with PWS in height, weight, body mass, strength, and agility.
Reports have indicated increase of growth rate (especially in the
first year of treatment) and a variety of other positive effects,
including improved body composition (higher muscle mass, lower fat
mass); improved weight management; increased energy and physical
activity; improved strength, agility, and endurance; and improved
respiratory function. The Prader-Willi Syndrome Association (USA)
recommends that a sleep study be conducted before initiating GH
treatment in a child with PWS. At this time there is no direct evidence
of a causative link between growth hormone and the respiratory problems
seen in PWS (among both those receiving and those not receiving GH
treatment), including sudden death. A follow-up sleep study after one
year of GH treatment may also be indicated. GH (specifically Pfizer's
version, Genotropin) is the only treatment that has received an FDA
indication for children with PWS. The FDA indication only applies to
children.
Children short because of intrauterine growth retardation are small for gestational age at birth for a variety of reasons. If early catch-up growth
does not occur and their heights remain below the third percentile by 2
or 3 years of age, adult height is likely to be similarly low.
High-dose GH treatment has been shown to accelerate growth, but data on
long term benefits and risks are limited.
Idiopathic short stature (ISS) is one of the most controversial indications for GH as pediatric endocrinologists do not agree on its definition, diagnostic criteria, or limits.
The term has been applied to children with severe unexplained shortness
that will result in an adult height below the 3rd percentile. In the
late 1990s, the pharmaceutical manufacturer Eli Lilly and Company sponsored trials of their brand of rHGH
(Humatrope) in children with extreme ISS, those at least 2.25 standard
deviations below mean (in the lowest 1.2 percent of the population).
These boys and girls appeared to be headed toward heights of less than
63" (160 cm) and 59" (150 cm) respectively. They were treated for about 4
years and gained 1.5–3 in (3.8–7.6 cm) in adult height. Controversy has
arisen as to whether all of these children were truly "short normal"
children, since the average IGF1
was low. Approval of HGH for the treatment of this extreme degree of
shortness led to an increase in the number of parents seeking its use to
make otherwise normal children a little taller.
Adverse effects
The New England Journal of Medicine published two editorials in 2003 expressing concern about off-label uses
of HGH and the proliferation of advertisements for "HGH-Releasing"
dietary supplements, and emphasized that there is no evidence that use
of HGH in healthy adults or in geriatric patients is safe and effective -
and especially emphasized that risks of long-term HGH treatment are
unknown. One editorial was by Jeffrey M. Drazen, M.D., the
editor-in-chief of the journal; the other one
was by Dr. Mary Lee Vance, who provided the NEJM's editorial original,
cautious comment on a much cited 1990 study on the use of HGH in
geriatric patients with low growth hormone levels.
A small but controlled study of GH given to severely ill adults in an intensive care
unit setting for the purpose of increasing strength and reducing the
muscle wasting of critical illness showed a higher mortality rate for
the patients having received GH. The reason is unknown, but GH is now rarely used in ICU patients unless they have severe growth hormone deficiency.
GH treatment usually decreases insulin sensitivity, but some studies showed no evidence for increased diabetes incidence in GH-treated adult hypopituitary patients.
In past it was believed that GH treatment could increase the cancer
risk; a large study recently concluded that "With relatively short
follow-up, the overall primary cancer risk in 6840 patients receiving GH
as adults was not increased. Elevated SIRs (which is risk of getting
cancer) were found for subgroups in the USA cohort defined by age <35 childhood="" deficiency.="" gh="" onset="" or="" p="" years="">
The FDA issued a Safety Alert in August 2011, communicating the
fact that a French study found that persons with certain kinds of short
stature (idiopathic growth hormone deficiency and idiopathic or gestational short stature)
treated with recombinant human growth hormone during childhood and who
were followed over a long period of time, were at a small increased risk
of death when compared to individuals in the general population of
France.
History
Perhaps the most famous person who exemplified the appearance of untreated congenital growth hormone deficiency was Charles Sherwood Stratton (1838–1883), who was exhibited by P. T. Barnum as General Tom Thumb,
and married Lavinia Warren. Pictures of the couple show the typical
adult features of untreated severe growth hormone deficiency. Despite
the severe shortness, limbs and trunks are proportional.
Like many other nineteenth-century medical terms that lost precise meaning as they gained wider currency, “midget”,
as a term for someone with extreme proportional shortness, acquired
pejorative connotations and is no longer used in medical contexts.
By the middle of the twentieth century, endocrinologists
understood the clinical features of growth hormone deficiency. GH is a
protein hormone, like insulin, which had been purified from pig and cow pancreases
for treatment of type 1 diabetes since the 1920s. However, pig and cow
GH did not work at all in humans, due to greater species-to-species
variation of molecular structure (i.e., insulin is considered more
"evolutionarily conserved" than GH).
Extraction for treatment
Extracted growth hormone was used since the late 1950s until the late 1980s when its use was replaced by recombinant GH.
In the late 1950s, Maurice Raben purified enough GH from human pituitary glands
to successfully treat a GH-deficient boy. A few endocrinologists began
to help parents of severely GH-deficient children to make arrangements
with local pathologists to collect human pituitary glands after removal at autopsy. Parents would then contract with a biochemist to purify enough growth hormone to treat their child. Few families could manage such a complicated undertaking.
In 1960, the National Pituitary Agency was formed as a branch of the U.S. National Institutes of Health.
The purpose of this agency was to supervise the collection of human
pituitary glands when autopsies were performed, arrange for large-scale
extraction and purification of GH, and distribute it to a limited number
of pediatric endocrinologists for treating GH-deficient children under
research protocols. Canada, UK, Australia, New Zealand, France, Israel,
and other countries establish similar government-sponsored agencies to
collect pituitaries, purify GH, and distribute it for treatment of
severely GH-deficient children.
Supplies of this “cadaver growth hormone” were limited, and only
the most severely deficient children were treated. From 1963 to 1985
about 7700 children in the U.S. and 27,000 children worldwide were given
GH extracted from human pituitary glands to treat severe GH deficiency.
Physicians trained in the relatively new specialty of pediatric endocrinology
provided most of this care, but in the late 1960s there were only a
hundred of these physicians in a few dozen of the largest university
medical centers around the world.
In 1977, the NPA GH extraction and purification procedure was refined and improved.
A shortage of available cadaver GH worsened in the late 1970s as
the autopsy rate in the U.S. declined, while the number of pediatric
endocrinologists able to diagnose and treat GH deficiency increased. GH
was "rationed." Often, treatment would be stopped when a child reached
an arbitrary minimal height, such as 5 ft 0 in (1.52 m). Children who
were short for reasons other than severe GH deficiency were lied to and
told that they would not benefit from treatment. Only those pediatric
endocrinologists that remained at university medical centers with
departments able to support a research program had access to NPA growth
hormone.
In the late 1970s, a Swedish pharmaceutical company, Kabi,
contracted with a number of hospitals in Europe to buy pituitary glands
for the first commercial GH product, Crescormon. Although an additional
source of GH was welcomed, Crescormon was greeted with ambivalence by
pediatric endocrinologists in the United States. The first concern was
that Kabi would begin to purchase pituitaries in the U.S., which would
quickly undermine the NPA, which relied on a donation system like blood
transfusion.
As the number of autopsies continued to shrink, would pathologists sell
pituitaries to a higher bidder? The second offense was Kabi-Pharmacia’s
marketing campaign, which was directed at primary care physicians
under the slogan, “Now, you determine the need,” implying that the
services of a specialist were not needed for growth hormone treatment
anymore and that any short child might be a candidate for treatment.
Although the Crescormon controversy in the U.S. is long forgotten,
Kabi’s pituitary purchase program continued to generate scandal in
Europe as recently as 2000.
Recombinant human growth hormone (rHGH)
In
1981, the new American corporation Genentech, after collaboration with
Kabi, developed and started trials of recombinant human growth hormone
(rHGH) made by a new technology (recombinant DNA) in which human genes
were inserted into bacteria so that they could produce unlimited
amounts of the protein. Because this was new technology, approval was
deferred as lengthy safety trials continued over the next four years.
In 1985, four young adults in the U.S. having received NPA growth hormone in the 1960s developed CJD (Creutzfeldt–Jakob disease).
The connection was recognized within a few months, and use of human
pituitary GH rapidly ceased. Between 1985 and 2003, a total of 26 cases
of CJD occurred in adults having received NPA GH before 1977 (out of
7700), comparable numbers of cases occurred around the world. By 2003
there had been no cases in people who received only GH purified by the
improved 1977 methods.
Discontinuation of human cadaver growth hormone led to rapid Food
and Drug Administration approval of Genentech’s recombinant human
growth hormone, which was introduced in 1985 as Protropin in the
United States. Although this previously scarce commodity was suddenly
available in "bucketfuls", the price of treatment (US$10,000–30,000 per
year) was the highest at the time. Genentech justified it by the
prolonged research and development investment, orphan drug status, and a pioneering post-marketing surveillance registry for tracking safety and effectiveness (National Cooperative Growth Study).
Within a few years, GH treatment had become more common and competitors entered the market. Eli Lilly launched a competing natural sequence growth hormone (Humatrope). Pharmacia (formerly Kabi, now Pfizer) introduced Genotropin. Novo Nordisk introduced Norditropin. Serono
(now EMD Serono) introduced Saizen and Serostim. Ferring has introduced
Zomacton. Genentech eventually introduced another HGH product,
Nutropin, and stopped making Protropin in 2004. Price competition had
begun. Teva, which is primarily a generics company, has introduced
Tev-tropin. Chinese companies have entered the market as well and have
introduced more pricing competition: NeoGenica BioScience Ltd.
introduced Hypertropin, GeneScience introduced Jintropin, Anhui Anke
Biotechnology introduced Ansomone, Shanghai United Kefei Biotechnology
introduced Kefei HGH,
and Hygene BioPharm introduced Hygetropin. These are all recombinant
human growth hormone products and they have competed with various
marketing strategies. Most children with severe deficiency in the
developed world are now likely to have access to a pediatric
endocrinologist and be diagnosed and offered treatment.
Pediatric endocrinology
became a recognizable specialty in the 1950s, but did not reach board
status in the U.S. until the late 1970s. Even 10 years later, as a
cognitive, procedureless specialty dealing with mostly rare diseases, it
was one of the smallest, lowest-paid, and more obscure of the medical
specialities. Pediatric endocrinologists were the only physicians interested in the arcana of GH metabolism and children’s growth, but their previously academic arguments took on new practical significance with major financial implications.
The major scientific arguments dated back to the days of GH scarcity:
Everyone agrees on the nature and diagnosis of severe GH deficiency, but what are the edges and variations?
How should marked constitutional delay be distinguished from partial GH deficiency?
To what extent is "normal shortness" a matter of short children naturally making less growth hormone?
Can a child make GH in response to a stimulation test but fail to make enough in "daily life" to grow normally?
If a stimulation test is used to define deficiency, what GH cutoff should be used to define normal?
It was the ethical
questions that were new. Is GH not a wise use of finite healthcare
resources, or is the physician’s primary responsibility to the patient?
If GH is given to most extremely short children to make them taller,
will the definition of “extremely short” simply rise, negating the
expected social benefit? If GH is given to short children whose parents
can afford it, will shortness become a permanent mark of lower social
origins? More of these issues are outlined in the ethics section. Whole
meetings were devoted to these questions; pediatric endocrinology had
become a specialty with its own bioethics issues.
Despite the price, the 1990s became an era of experimentation to
see what else growth hormone could help. The medical literature of the
decade contains hundreds of reports of small trials of GH use in nearly
every type of growth failure and shortness imaginable. In most cases,
the growth responses were modest.
For conditions with a large enough potential market, more rigorous
trials were sponsored by pharmaceutical companies that were making
growth hormone to achieve approval to market for those specific
indications. Turner syndrome and chronic kidney failure were the first of these “nonGH-deficient causes of shortness” to receive FDA approval for GH treatment, and Prader-Willi syndrome and intrauterine growth retardation followed. Similar expansion of use occurred in Europe.
One obvious potential market was adult GH deficiency. By the
mid-1990s, several GH companies had sponsored or publicized research
into the quality of life of adults with severe GH deficiency. Most were people having been treated with GH in childhood for severe deficiency.
Although the injections are painless, many of them had been happy to
leave injections behind as they reached final heights in the low-normal
range.
However, as adults in their 30s and 40s, these people, who had been
children with growth hormone deficiency, were now adults with growth
hormone deficiency and had more than their share of common adult
problems: reduced physical, mental, and social energy, excess adipose
and diminished muscle, diminished libido, poor bone density, higher
cholesterol levels, and higher rates of cardiovascular disease. Research
trials soon confirmed that a few months of GH could improve nearly all
of these parameters. However, despite marketing efforts, most
GH-deficient adults remain untreated.
Though GH use was slow to be accepted among adults with GH
deficiency, similar research to see if GH treatment could slow or
reverse some of the similar effects of aging attracted much public
interest. The most publicized trial was reported by Daniel Rudman in
1990. As with other types of hormone supplementation for aging (testosterone, estrogen, DHEA), confirmation of benefit and accurate understanding of risks has been only slowly evolving.
In 1997, Ronald Klatz of the American Academy of Anti-Aging Medicine published Grow Young With HGH: The Amazing Medically Proven Plan To Reverse the Effects Of Aging, an uncritical touting of GH as the answer to aging.
This time, the internet amplified the proposition and spawned a hundred
frauds and scams. However, their adoption of the "HGH" term has
provided an easy way to distinguish the hype from the evidence. In
2003, growth hormone hit the news again, when the US FDA granted Eli Lilly approval to market Humatrope for the treatment of idiopathic short stature.
The indication was controversial for several reasons, the primary one
being the difficulty in defining extreme shortness with normal test
results as a disease rather than the extreme end of the normal height
range.
Recombinant growth hormone available in the U.S. (and their manufacturers) included Nutropin (Genentech), Humatrope (Eli Lilly and Company), Genotropin (Pfizer), Norditropin (Novo Nordisk), Tev-Tropin (Teva) and Saizen (Merck Serono).
The products are nearly identical in composition, efficacy, and cost,
varying primarily in the formulations and delivery devices.
Terminology
Growth hormone
(GH l) is also called somatotropin (British: somatotrophin). The human
form of growth hormone is known as human growth hormone, or hGH (ovine
growth hormone, or sheep growth hormone, is abbreviated oGH). GH can
refer either to the natural hormone produced by the pituitary
(somatotropin), or biosynthetic GH for therapy.
Cadaver growth hormone is the term for GH extracted from the pituitary glands of human cadavers between 1960 and 1985 for therapy of deficient children. In the U.S., cadaver GH, also referred to as NPA growth hormone,
was provided by the National Pituitary Agency, and by other national
programs and commercial firms as well. In 1985 it was associated with
the development of Creutzfeldt–Jakob disease, and was withdrawn from use.
RHGH (rHGH, rhGH) refers to recombinant human growth hormone, that is, somatropin (INN). Its amino acid sequence is identical with that of endogenous human GH.
It is coincidental that RHGH also refers to rhesus monkey GH (RhGH), using the accepted naming convention of Rh for rhesus. Rhesus growth hormone was never used by physicians to treat human patients, but rhesus GH was part of the lore of the underground anabolic steroid community in those years, and fraudulent versions may have been bought and sold in gyms.
met-GH refers to methionyl–growth hormone, that is, somatrem (INN). This was the first recombinant GH product marketed (trade name Protropin by Genentech). It had the same amino acid sequence as human GH with an extra methionine at the end of the chain to facilitate the manufacturing process. It was discontinued in 2004.
rBST refers to recombinant bovine somatotropin (cow growth hormone), or recombinant bovine GH (rbGH, RBGH).
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