Chromosomal translocation

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https://en.wikipedia.org/wiki/Chromosomal_translocation 

 

Chromosomal reciprocal translocation of the 4th and 20th chromosome.

In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes balanced and unbalanced translocation, with two main types: reciprocal-, and Robertsonian translocation. Reciprocal translocation is a chromosome abnormality caused by exchange of parts between non-homologous chromosomes. Two detached fragments of two different chromosomes are switched. Robertsonian translocation occurs when two non-homologous chromosomes get attached, meaning that given two healthy pairs of chromosomes, one of each pair "sticks" together.

A gene fusion may be created when the translocation joins two otherwise-separated genes. It is detected on cytogenetics or a karyotype of affected cells. Translocations can be balanced (in an even exchange of material with no genetic information extra or missing, and ideally full functionality) or unbalanced (where the exchange of chromosome material is unequal resulting in extra or missing genes).

Reciprocal translocations

Reciprocal translocations are usually an exchange of material between non-homologous chromosomes. Estimates of incidence range from about 1 in 500 to 1 in 625 human newborns. Such translocations are usually harmless and may be found through prenatal diagnosis. However, carriers of balanced reciprocal translocations have increased risks of creating gametes with unbalanced chromosome translocations, leading to Infertility, miscarriages or children with abnormalities. Genetic counseling and genetic testing are often offered to families that may carry a translocation. Most balanced translocation carriers are healthy and do not have any symptoms.

It is important to distinguish between chromosomal translocations occurring in gametogenesis, due to errors in meiosis, and translocations that occur in cellular division of somatic cells, due to errors in mitosis. The former results in a chromosomal abnormality featured in all cells of the offspring, as in translocation carriers. Somatic translocations, on the other hand, result in abnormalities featured only in the affected cell line, as in chronic myelogenous leukemia with the Philadelphia chromosome translocation.

Nonreciprocal translocation

Nonreciprocal translocation involves the one-way transfer of genes from one chromosome to another nonhomologous chromosome.

Robertsonian translocations

Robertsonian translocation is a type of translocation caused by breaks at or near the centromeres of two acrocentric chromosomes. The reciprocal exchange of parts gives rise to one large metacentric chromosome and one extremely small chromosome that may be lost from the organism with little effect because it contains few genes. The resulting karyotype in humans leaves only 45 chromosomes, since two chromosomes have fused together. This has no direct effect on the phenotype, since the only genes on the short arms of acrocentrics are common to all of them and are present in variable copy number (nucleolar organiser genes).

Robertsonian translocations have been seen involving all combinations of acrocentric chromosomes. The most common translocation in humans involves chromosomes 13 and 14 and is seen in about 0.97 / 1000 newborns. Carriers of Robertsonian translocations are not associated with any phenotypic abnormalities, but there is a risk of unbalanced gametes that lead to miscarriages or abnormal offspring. For example, carriers of Robertsonian translocations involving chromosome 21 have a higher risk of having a child with Down syndrome. This is known as a 'translocation Downs'. This is due to a mis-segregation (nondisjunction) during gametogenesis. The mother has a higher (10%) risk of transmission than the father (1%). Robertsonian translocations involving chromosome 14 also carry a slight risk of uniparental disomy 14 due to trisomy rescue.

Role in disease

Some human diseases caused by translocations are:

• Cancer: Several forms of cancer are caused by acquired translocations (as opposed to those present from conception); this has been described mainly in leukemia (acute myelogenous leukemia and chronic myelogenous leukemia). Translocations have also been described in solid malignancies such as Ewing's sarcoma.
• Infertility: One of the would-be parents carries a balanced translocation, where the parent is asymptomatic but conceived fetuses are not viable.
• Down syndrome is caused in a minority (5% or less) of cases by a Robertsonian translocation of the chromosome 21 long arm onto the long arm of chromosome 14.

Chromosomal translocations between the sex chromosomes can also result in a number of genetic conditions, such as

• XX male syndrome: caused by a translocation of the SRY gene from the Y to the X chromosome

By chromosome

Overview of some chromosomal translocations involved in different cancers, as well as implicated in some other conditions, e.g. schizophrenia, with chromosomes arranged in standard karyogram order. Abbreviations:
ALL – Acute lymphoblastic leukemia
AML – Acute myeloid leukemia
CML – Chronic myelogenous leukemia
DFSP – Dermatofibrosarcoma protuberans

Denotation

The International System for Human Cytogenetic Nomenclature (ISCN) is used to denote a translocation between chromosomes. The designation t(A;B)(p1;q2) is used to denote a translocation between chromosome A and chromosome B. The information in the second set of parentheses, when given, gives the precise location within the chromosome for chromosomes A and B respectively—with p indicating the short arm of the chromosome, q indicating the long arm, and the numbers after p or q refers to regions, bands and subbands seen when staining the chromosome with a staining dye. See also the definition of a genetic locus. The translocation is the mechanism that can cause a gene to move from one linkage group to another.

Examples

For an explanation of the symbols and abbreviations used in these examples, see Cytogenetic notation.

Translocation	Associated diseases	Fused genes/proteins
		First	Second
t(8;14)(q24;q32)	Burkitt's lymphoma	c-myc on chromosome 8, gives the fusion protein lymphocyte-proliferative ability	IGH@ (immunoglobulin heavy locus) on chromosome 14, induces massive transcription of fusion protein
t(11;14)(q13;q32)	Mantle cell lymphoma	cyclin D1 on chromosome 11, gives fusion protein cell-proliferative ability	IGH@ (immunoglobulin heavy locus) on chromosome 14, induces massive transcription of fusion protein
t(14;18)(q32;q21)	Follicular lymphoma (~90% of cases)	IGH@ (immunoglobulin heavy locus) on chromosome 14, induces massive transcription of fusion protein	Bcl-2 on chromosome 18, gives fusion protein anti-apoptotic abilities
t(10;(various))(q11;(various))	Papillary thyroid cancer	RET proto-oncogene[15] on chromosome 10	PTC (Papillary Thyroid Cancer) – Placeholder for any of several other genes/proteins
t(2;3)(q13;p25)	Follicular thyroid cancer	PAX8 – paired box gene 8 on chromosome 2	PPARγ1 (peroxisome proliferator-activated receptor γ 1) on chromosome 3
t(8;21)(q22;q22)[14]	Acute myeloblastic leukemia with maturation	ETO on chromosome 8	AML1 on chromosome 21 found in ~7% of new cases of AML, carries a favorable prognosis and predicts good response to cytosine arabinoside therapy
t(9;22)(q34;q11) Philadelphia chromosome	Chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL)	Abl1 gene on chromosome 9	BCR ("breakpoint cluster region" on chromosome 22
t(15;17)(q22;q21)[14]	Acute promyelocytic leukemia	PML protein on chromosome 15	RAR-α on chromosome 17 persistent laboratory detection of the PML-RARA transcript is strong predictor of relapse
t(12;15)(p13;q25)	Acute myeloid leukemia, congenital fibrosarcoma, secretory breast carcinoma, mammary analogue secretory carcinoma of salivary glands, cellular variant of mesoblastic nephroma	TEL on chromosome 12	TrkC receptor on chromosome 15
t(9;12)(p24;p13)	CML, ALL	JAK on chromosome 9	TEL on chromosome 12
t(12;16)(q13;p11)	Myxoid liposarcoma	DDIT3 (formerly CHOP) on chromosome 12	FUS gene on chromosome 16
t(12;21)(p12;q22)	ALL	TEL on chromosome 12	AML1 on chromosome 21
t(11;18)(q21;q21)	MALT lymphoma	BIRC3 (API-2)	MLT
t(1;11)(q42.1;q14.3)	Schizophrenia
t(2;5)(p23;q35)	Anaplastic large cell lymphoma	ALK	NPM1
t(11;22)(q24;q11.2-12)	Ewing's sarcoma	FLI1	EWS
t(17;22)	DFSP	Collagen I on chromosome 17	Platelet derived growth factor B on chromosome 22
t(1;12)(q21;p13)	Acute myelogenous leukemia
t(X;18)(p11.2;q11.2)	Synovial sarcoma
t(1;19)(q10;p10)	Oligodendroglioma and oligoastrocytoma
t(17;19)(q22;p13)	ALL
t(7,16) (q32-34;p11) or t(11,16) (p11;p11)	Low-grade fibromyxoid sarcoma	FUS	CREB3L2 or CREB3L1

History

In 1938, Karl Sax, at the Harvard University Biological Laboratories, published a paper entitled "Chromosome Aberrations Induced by X-rays", which demonstrated that radiation could induce major genetic changes by affecting chromosomal translocations. The paper is thought to mark the beginning of the field of radiation cytology, and led him to be called "the father of radiation cytology".

Hematopoietic stem cell

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Hematopoietic_stem_cell 

 

Haematopoietic stem cell
Overview of normal human haematopoiesis
Details
System	Hematopoietic system
Location	Bone marrow
Function	Stem cells that give rise to other blood cells
Identifiers
Latin	Cellula haematopoietica praecursoria
Acronym(s)	HSC
MeSH	D006412
TH	H2.00.01.0.00006

Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. This process occurs in the red bone marrow, in the core of most bones. In embryonic development, the red bone marrow is derived from the layer of the embryo called the mesoderm.

Haematopoiesis is the process by which all mature blood cells are produced. It must balance enormous production needs (the average person produces more than 500 billion blood cells every day) with the need to regulate the number of each blood cell type in the circulation. In vertebrates, the vast majority of hematopoiesis occurs in the bone marrow and is derived from a limited number of hematopoietic stem cells that are multipotent and capable of extensive self-renewal.

Hematopoietic stem cells give rise to different types of blood cells, in lines called myeloid and lymphoid. Myeloid and lymphoid lineages both are involved in dendritic cell formation. Myeloid cells include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, and megakaryocytes to platelets. Lymphoid cells include T cells, B cells, natural killer cells, and innate lymphoid cells. The definition of hematopoietic stem cell has evolved since they were first discovered in 1961. The hematopoietic tissue contains cells with long-term and short-term regeneration capacities and committed multipotent, oligopotent, and unipotent progenitors. Hematopoietic stem cells constitute 1:10,000 of cells in myeloid tissue.

HSC transplants are used in the treatment of cancers and other immune system disorders.

Structure

They are round, non-adherent, with a rounded nucleus and low cytoplasm-to-nucleus ratio. In shape, hematopoietic stem cells resemble lymphocytes.

Location

Hematopoietic stem cells are found in the bone marrow of adults, especially in the pelvis, femur, and sternum. They are also found in umbilical cord blood and, in small numbers, in peripheral blood.

Stem and progenitor cells can be taken from the pelvis, at the iliac crest, using a needle and syringe. The cells can be removed as liquid (to perform a smear to look at the cell morphology) or they can be removed via a core biopsy (to maintain the architecture or relationship of the cells to each other and to the bone).

Subtypes

A colony-forming unit is a subtype of HSC. (This sense of the term is different from colony-forming units of microbes, which is a cell counting unit.) There are various kinds of HSC colony-forming units:

• Colony-forming unit–granulocyte-erythrocyte-monocyte-megakaryocyte (CFU-GEMM)
• Colony-forming unit–lymphocyte (CFU-L)
• Colony-forming unit–erythrocyte (CFU-E)
• Colony-forming unit–granulocyte-macrophage (CFU-GM)
• Colony-forming unit–megakaryocyte (CFU-Meg)
• Colony-forming unit–basophil (CFU-B)
• Colony-forming unit–eosinophil (CFU-Eos)

The above CFUs are based on the lineage. Another CFU, the colony-forming unit–spleen (CFU-S), was the basis of an in vivo clonal colony formation, which depends on the ability of infused bone marrow cells to give rise to clones of maturing hematopoietic cells in the spleens of irradiated mice after 8 to 12 days. It was used extensively in early studies, but is now considered to measure more mature progenitor or transit-amplifying cells rather than stem cells.

Isolating stem cells

Since hematopoietic stem cells cannot be isolated as a pure population, it is not possible to identify them in a microscope. Hematopoietic stem cells can be identified or isolated by the use of flow cytometry where the combination of several different cell surface markers (particularly CD34) are used to separate the rare Hematopoietic stem cells from the surrounding blood cells. Hematopoietic stem cells lack expression of mature blood cell markers and are thus called Lin-. Lack of expression of lineage markers is used in combination with detection of several positive cell-surface markers to isolate hematopoietic stem cells. In addition, hematopoietic stem cells are characterised by their small size and low staining with vital dyes such as rhodamine 123 (rhodamine ^lo) or Hoechst 33342 (side population).

Function

Diagram of cells that arise from Hematopoetic stem cells during the process of hematopoiesis.

Haematopoiesis

Hematopoietic stem cells are essential to haematopoiesis, the formation of the cells within blood. Hematopoietic stem cells can replenish all blood cell types (i.e., are multipotent) and self-renew. A small number of Hematopoietic stem cells can expand to generate a very large number of daughter Hematopoietic stem cells. This phenomenon is used in bone marrow transplantation, when a small number of Hematopoietic stem cells reconstitute the hematopoietic system. This process indicates that, subsequent to bone marrow transplantation, symmetrical cell divisions into two daughter Hematopoietic stem cells must occur.

Stem cell self-renewal is thought to occur in the stem cell niche in the bone marrow, and it is reasonable to assume that key signals present in this niche will be important in self-renewal. There is much interest in the environmental and molecular requirements for HSC self-renewal, as understanding the ability of HSC to replenish themselves will eventually allow the generation of expanded populations of HSC in vitro that can be used therapeutically.

Quiescence

Hematopoietic stem cells, like all adult stem cells, mostly exist in a state of quiescence, or reversible growth arrest. The altered metabolism of quiescent HCSs helps the cells survive for extended periods of time in the hypoxic bone marrow environment. When provoked by cell death or damage, Hematopoietic stem cells exit quiescence and begin actively dividing again. The transition from dormancy to propagation and back is regulated by the MEK/ERK pathway and PI3K/AKT/mTOR pathway. Dysregulation of these transitions can lead to stem cell exhaustion, or the gradual loss of active Hematopoietic stem cells in the blood system.

Mobility

Hematopoietic stem cells have a higher potential than other immature blood cells to pass the bone marrow barrier, and, thus, may travel in the blood from the bone marrow in one bone to another bone. If they settle in the thymus, they may develop into T cells. In the case of fetuses and other extramedullary hematopoiesis, Hematopoietic stem cells may also settle in the liver or spleen and develop. 

This enables Hematopoietic stem cells to be harvested directly from the blood.

DNA damage with aging

DNA strand breaks accumulate in long term Hematopoietic stem cells during aging. This accumulation is associated with a broad attenuation of DNA repair and response pathways that depends on HSC quiescence. Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template. The NHEJ pathway depends on several proteins including ligase 4, DNA polymerase mu and NHEJ factor 1 (NHEJ1, also known as Cernunnos or XLF).

DNA ligase 4 (Lig4) has a highly specific role in the repair of double-strand breaks by NHEJ. Lig4 deficiency in the mouse causes a progressive loss of Hematopoietic stem cells during aging. Deficiency of lig4 in pluripotent stem cells results in accumulation of DNA double-strand breaks and enhanced apoptosis.

In polymerase mu mutant mice, hematopoietic cell development is defective in several peripheral and bone marrow cell populations with about a 40% decrease in bone marrow cell number that includes several hematopoietic lineages. Expansion potential of hematopoietic progenitor cells is also reduced. These characteristics correlate with reduced ability to repair double-strand breaks in hematopoietic tissue. 

Deficiency of NHEJ factor 1 in mice leads to premature aging of hematopoietic stem cells as indicated by several lines of evidence including evidence that long-term repopulation is defective and worsens over time. Using a human induced pluripotent stem cell model of NHEJ1 deficiency, it was shown that NHEJ1 has an important role in promoting survival of the primitive hematopoietic progenitors. These NHEJ1 deficient cells possess a weak NHEJ1-mediated repair capacity that is apparently incapable of coping with DNA damages induced by physiological stress, normal metabolism, and ionizing radiation.

The sensitivity of haematopoietic stem cells to Lig4, DNA polymerase mu and NHEJ1 deficiency suggests that NHEJ is a key determinant of the ability of stem cells to maintain themselves against physiological stress over time. Rossi et al. found that endogenous DNA damage accumulates with age even in wild type Hematopoietic stem cells, and suggested that DNA damage accrual may be an important physiological mechanism of stem cell aging.

Clinical significance

Transplant

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).

It is most often performed for patients with certain cancers of the blood or bone marrow, such as multiple myeloma or leukemia. In these cases, the recipient's immune system is usually destroyed with radiation or chemotherapy before the transplantation. Infection and graft-versus-host disease are major complications of allogeneic HSCT.

In order to harvest stem cells from the circulating peripheral blood, blood donors are injected with a cytokine, such as granulocyte-colony stimulating factor (G-CSF), that induces cells to leave the bone marrow and circulate in the blood vessels. In mammalian embryology, the first definitive Hematopoietic stem cells are detected in the AGM (aorta-gonad-mesonephros), and then massively expanded in the fetal liver prior to colonising the bone marrow before birth.

Hematopoietic stem cell transplantation remains a dangerous procedure with many possible complications; it is reserved for patients with life-threatening diseases. As survival following the procedure has increased, its use has expanded beyond cancer to autoimmune diseases and hereditary skeletal dysplasias; notably malignant infantile osteopetrosis and mucopolysaccharidosis.

Research

Behavior in culture

A cobblestone area-forming cell (CAFC) assay is a cell culture-based empirical assay. When plated onto a confluent culture of stromal feeder layer, a fraction of Hematopoietic stem cells creep between the gaps (even though the stromal cells are touching each other) and eventually settle between the stromal cells and the substratum (here the dish surface) or trapped in the cellular processes between the stromal cells. Emperipolesis is the in vivo phenomenon in which one cell is completely engulfed into another (e.g. thymocytes into thymic nurse cells); on the other hand, when in vitro, lymphoid lineage cells creep beneath nurse-like cells, the process is called pseudoemperipolesis. This similar phenomenon is more commonly known in the HSC field by the cell culture terminology cobble stone area-forming cells (CAFC), which means areas or clusters of cells look dull cobblestone-like under phase contrast microscopy, compared to the other Hematopoietic stem cells, which are refractile. This happens because the cells that are floating loosely on top of the stromal cells are spherical and thus refractile. However, the cells that creep beneath the stromal cells are flattened and, thus, not refractile. The mechanism of pseudoemperipolesis is only recently coming to light. It may be mediated by interaction through CXCR4 (CD184) the receptor for CXC Chemokines (e.g., SDF1) and α4β1 integrins.

Repopulation kinetics

Hematopoietic stem cells (HSC) cannot be easily observed directly, and, therefore, their behaviors need to be inferred indirectly. Clonal studies are likely the closest technique for single cell in vivo studies of HSC. Here, sophisticated experimental and statistical methods are used to ascertain that, with a high probability, a single HSC is contained in a transplant administered to a lethally irradiated host. The clonal expansion of this stem cell can then be observed over time by monitoring the percent donor-type cells in blood as the host is reconstituted. The resulting time series is defined as the repopulation kinetic of the HSC.

The reconstitution kinetics are very heterogeneous. However, using symbolic dynamics, one can show that they fall into a limited number of classes. To prove this, several hundred experimental repopulation kinetics from clonal Thy-1^lo SCA-1⁺ lin⁻ c-kit⁺ HSC were translated into symbolic sequences by assigning the symbols "+", "-", "~" whenever two successive measurements of the percent donor-type cells have a positive, negative, or unchanged slope, respectively. By using the Hamming distance, the repopulation patterns were subjected to cluster analysis yielding 16 distinct groups of kinetics. To finish the empirical proof, the Laplace add-one approach was used to determine that the probability of finding kinetics not contained in these 16 groups is very small. By corollary, this result shows that the hematopoietic stem cell compartment is also heterogeneous by dynamical criteria. 

It was originally believed that all Hematopoietic stem cells were alike in their self-renewal and differentiation abilities. This view was first challenged by the 2002 discovery by the Muller-Sieburg group in San Diego, who illustrated that different stem cells can show distinct repopulation patterns that are epigenetically predetermined intrinsic properties of clonal Thy-1^lo Sca-1⁺ lin⁻ c-kit⁺ HSC. The results of these clonal studies led to the notion of lineage bias. Using the ratio ${\displaystyle \rho =L/M}$ of lymphoid (L) to myeloid (M) cells in blood as a quantitative marker, the stem cell compartment can be split into three categories of HSC. Balanced (Bala) Hematopoietic stem cells repopulate peripheral white blood cells in the same ratio of myeloid to lymphoid cells as seen in unmanipulated mice (on average about 15% myeloid and 85% lymphoid cells, or 3 ≤ ρ ≤ 10). Myeloid-biased (My-bi) Hematopoietic stem cells give rise to very few lymphocytes resulting in ratios 0 < ρ < 3, while lymphoid-biased (Ly-bi) Hematopoietic stem cells generate very few myeloid cells, which results in lymphoid-to-myeloid ratios of ρ > 10. All three types are normal types of HSC, and they do not represent stages of differentiation. Rather, these are three classes of HSC, each with an epigenetically fixed differentiation program. These studies also showed that lineage bias is not stochastically regulated or dependent on differences in environmental influence. My-bi HSC self-renew longer than balanced or Ly-bi HSC. The myeloid bias results from reduced responsiveness to the lymphopoetin interleukin 7 (IL-7).

Subsequently, other groups confirmed and highlighted the original findings. For example, the Eaves group confirmed in 2007 that repopulation kinetics, long-term self-renewal capacity, and My-bi and Ly-bi are stably inherited intrinsic HSC properties. In 2010, the Goodell group provided additional insights about the molecular basis of lineage bias in side population (SP) SCA-1⁺ lin⁻ c-kit⁺ HSC. As previously shown for IL-7 signaling, it was found that a member of the transforming growth factor family (TGF-beta) induces and inhibits the proliferation of My-bi and Ly-bi HSC, respectively.

B cell

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/B_cell 

 

B lymphocyte cell
Transmission electron micrograph of a human B cell
Details
System	Immune system
Identifiers
Latin	lymphocytus B
MeSH	D001402
FMA	62869

 

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

 

3D rendering of a B cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Additionally, B cells present antigens (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, (B for bursa) and not from bone marrow as commonly believed.

B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors (BCRs) on their cell membrane. BCRs allow the B cell to bind to a specific antigen, against which it will initiate an antibody response.

Development

B cells develop from hematopoietic stem cells (HSCs) that originate from bone marrow. HSCs first differentiate into multipotent progenitor (MPP) cells, then common lymphoid progenitor (CLP) cells. From here, their development into B cells occurs in several stages (shown in image to the right), each marked by various gene expression patterns and immunoglobulin H chain and L chain gene loci arrangements, the latter due to B cells undergoing V(D)J recombination as they develop.

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. 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 (T_H) cells, typically follicular T helper (T_FH) 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.^[16] 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.^[17] 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 T_FH 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 (T_H) cells, typically memory follicular T helper (T_FH) 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 T_FH 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.
• Lymphoplasmacytoid cell - A cell with a mixture of B lymphocyte and plasma cell morphological features that is thought to be closely related to or a subtype of plasma cells. This cell type is found in pre-malignant and malignant plasma cell dyscrasias that are associated with the secretion of IgM monoclonal proteins; these dyscrasias include IgM monoclonal gammopathy of undetermined significance and Waldenström's macroglobulinemia.
• 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.

B cell-related pathology

Autoimmune disease can result from abnormal B cell recognition of self-antigens followed by the production of autoantibodies. Autoimmune diseases where disease activity is correlated with B cell activity include scleroderma, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, post-infectious IBS, and rheumatoid arthritis.

Malignant transformation of B cells and their precursors can cause a host of cancers, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, follicular lymphoma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, and plasma cell malignancies such as multiple myeloma, Waldenström's macroglobulinemia, and certain forms of amyloidosis.

Epigenetic

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.

Immunosenescence

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Immunosenescence 

 

Immunosenescence refers to the gradual deterioration of the immune system brought on by natural age advancement. The adaptive immune system is affected more than the innate immune system.

Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory, especially by vaccination. This age-associated immune deficiency is ubiquitous and found in both long- and short-living species as a function of their age relative to life expectancy rather than chronological time. It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly.

Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely repeat an evolutionary pattern and most of the parameters affected by immunosenescence appear to be under genetic control. Immunosenescence can also be sometimes envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of antigens such as viruses and bacteria.

Overview of the age-associated decline in immune function

Immunosenescence is a multifactorial condition leading to many pathologically significant health problems in the aged population. Some of the age-dependent biological changes that contribute to the onset of immunosenescence are listed below:

• Hematopoietic stem cells (HSC), which provide the regulated lifelong supply of leukocyte progenitors that are in turn able to differentiate into a diversity of specialised immune cells (including lymphocytes, antigen-presenting dendritic cells and phagocytes) diminish in their self-renewal capacity. This is due to the accumulation of oxidative damage to DNA by aging and cellular metabolic activity and the shortening of telomeric terminals of chromosomes.
• There is a notable decline in the total number of phagocytes in aged hosts, coupled with an intrinsic reduction of their bactericidal activity.
• The cytotoxicity of Natural Killer (NK) cells and the antigen-presenting function of dendritic cells is known to diminish with old age. The age-associated impairment of dendritic Antigen Presenting Cells (APCs) has profound implications as this translates into a deficiency in cell-mediated immunity and thus, the inability for effector T-lymphocytes to modulate an adaptive immune response (see below).
• A decline in humoral immunity caused by a reduction in the population of antibody producing B-cells along with a smaller immunoglobulin diversity and affinity.

As age advances, there is decline in both the production of new naive lymphocytes and the functional competence of memory cell populations. This has been implicated in the increasing frequency and severity of diseases such as cancer, chronic inflammatory disorders, breakthrough infections and autoimmunity.  A problem of infections in the elderly is that they frequently present with non-specific signs and symptoms, and clues of focal infection are often absent or obscured by underlying chronic conditions. Ultimately, this provides problems in diagnosis and subsequently, treatment. 

In addition to changes in immune responses, the beneficial effects of inflammation devoted to the neutralisation of dangerous and harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging. It should be further noted that changes in the lymphoid compartment is not solely responsible for the malfunctioning of the immune system in the elderly. Although myeloid cell production does not seem to decline with age, macrophages become dysregulated as a consequence of environmental changes.

T-cell functional dysregulation as a biomarker for immunosenescence

The functional capacity of T-cells is most influenced by the effects of aging. In fact, age-related alterations are evident in all stages of T-cell development, making them a significant factor in the development of immunosenescence. After birth, the decline of T-cell function begins with the progressive involution of the thymus, which is the organ essential for T-cell maturation following the migration of precursor cells from the bone marrow. This age-associated decrease of thymic epithelial volume results in a reduction/exhaustion on the number of thymocytes (i.e. pre-mature T-cells), thus reducing output of peripheral naïve T-cells. Once matured and circulating throughout the peripheral system, T-cells still undergo deleterious age-dependent changes. Together with the age-related thymic involution, and the consequent age-related decrease of thymic output of new T cells, this situation leaves the body practically devoid of virgin T cells, which makes the body more prone to a variety of infectious and non-infectious diseases.

By age 40, and estimated 50% to 85% of adults have contracted human cytomegalivirus (HCMV), which is believed to be a major cause of immunosenescence, although this is controversial.^[21] Despite the fact that an average of 10% (and up to 50%) of the CD4 and CD8 memory T cells of HCMV-infected persons may be CMV-specific, these persons do not have a higher fatality rate resulting from other infections.

T-cell components associated with immunosenescence include:

• reduction in the CD4+/CD8+ ratio
• impaired development of CD4+ T follicular helper cells, which are specialized in facilitating peripheral B cell maturation, and the generation of antibody-producing plasma cells and memory B cells
• deregulation of intracellular signal transduction capabilities
• diminished capacity to produce effector lymphokines
• shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity
• cytotoxic activity of Natural Killer T-cells (NKTs) decreases
• impaired proliferation in response to antigenic stimulation
• the accumulation and the clonal expansion of memory and effector T-cells
• hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells
• changes in cytokine profile e.g. increased pro-inflammatory cytokines milieu present in the elderly