Hematopoietic stem cell

From Wikipedia, the free encyclopedia

Note that some complexity is omitted from the diagram. Lymphocytes come from "Lymphoid" line,
while granulocytes, monocytes, megakaryocytes, and erythrocytes come from "Myeloid" line. Among
myeloid cells, granulocytes and monocytes have a common precursor, "CFU-GM".

Hematopoietic stem cells (HSC) are stem cells which give rise to all the blood cell types including
myeloid (monocytes and macrophages, neutrophils, basophils, eosinophils, erythrocytes,
megakaryocytes/platelets, dendritic cells) and lymphoid lineages (T-cells, B-cells, NK-cells). The
definition of hematopoietic stem cells has undergone considerable revision in the last two decades.
The hematopoietic tissue contains cells with long term and short term regeneration capacities and
committed multipotent, oligopotent and unipotent progenitors. Recently, long-term transplantation
experiments point towards a clonal diversity model of hematopoietic stem cells. Here, the HSC
compartment consists of a fixed number of different types of HSC, each with epigenetically
preprogrammed behavior. This contradicts older models of HSC behavior, which postulated a single
type of HSC that can be continuously molded into different subtypes of HSC.

A monocyte is a leukocyte, part of the human body's immune system that protects against blood-
borne pathogens and moves quickly (aprox. 8-12 hours) to sites of infection in the tissues. Monocytes
are usually identified in stained smears by their large bilobate nucleus.


Physiology

Monocyte

Monocytes are produced by the bone marrow from haematopoietic stem cell precursors called
monoblasts. Monocytes circulate in the bloodstream for about one to three days and then typically
move into tissues throughout the body. They constitute between three to eight percent of the
leukocytes in the blood. In the tissues monocytes mature into different types of macrophages at
different anatomical locations.

Monocytes are responsible for phagocytosis (ingestion) of foreign substances in the body. Monocytes
can perform phagocytosis using intermediary (opsonising) proteins such as antibodies or complement
that coat the pathogen, as well as by binding to the microbe directly via pattern-recognition receptors
that recognize pathogens. Monocytes are also capable of killing infected host cells via antibody,
termed antibody-mediated cellular cytotoxicity. Vacuolization may be present in a cell that has
recently phagocytized foreign matter.

Monocytes which migrate from the bloodstream to other tissues are called macrophages.
Macrophages are responsible for protecting tissues from foreign substances but are also suspected
to be the predominant cells involved in triggering atherosclerosis. They are cells that possess a large
smooth nucleus, a large area of cytoplasm and many internal vesicles for processing foreign material.

Diagnostic use
A scanning electron microscope (SEM) image of normal circulating human blood. One can see red
blood cells, several knobby white blood cells including lymphocytes, a monocyte, a neutrophil, and
many small disc-shaped platelets.

A monocyte count is part of a complete blood count and is expressed either as a ratio of monocytes
to the total number of white blood cells counted, or by absolute numbers. Both may be useful in
determining or refuting a possible diagnosis. Monocytosis is the state of excess monocytes in the
peripheral blood. It may be indicative of various disease states. Examples of processes that can
increase a monocyte count include:
-chronicinflammation
-stressresponse
-hyperadrenocorticism
-immune-mediateddisease
-pyogranulomatousdisease
-necrosis
- red cell regeneration
Proerythroblast

A proerythroblast (or rubriblast, or pronormoblast) is the earliest of four stages in development of

the normoblast.

 In histology, it is very difficult to distinguish it from the other "blast" cells (lymphoblast,
myeloblast, monoblast, and megakaryoblast.) The cytoplasm is blue in an H&E stain,
indicating that it is basophilic.

"Pronormoblast" vs. "proerythroblast"

Some sources consider the terms "pronormoblast" and "proerythroblast" to be synonyms. [1] However,
other sources[2] consider "proerythroblast" to be a parent term, divided into the following two
categories:

 "pronormoblast" - normal develoment

 "promegaloblast" - abnormal development

The root for CFU-E is "rubri", for CFU-GM is "granulo" or "myelo" and "mono", for CFU-L is "lympho"
and for CFU-Me is "megakaryo". According to this terminology, the stages of red blood cell formation
would be: rubriblast, prorubricyte, rubricyte, metarubricyte and finally erythrocyte. However, the
following nomenclature seems to be, at present, the most prevalent:

Committe
"lympho" "rubri" "granulo" or "myelo" "mono" "megakaryo"
e
Lineage Lymphoid Myeloid Myeloid Myeloid Myeloid
CFU CFU-L CFU-E CFU-GM CFU-GM CFU-Me
lymphocytopoi monocytopoi thrombocytopoi
Process erythropoiesis granulocytopoiesis
esis esis esis
Proerythroblas Megakaryoblas
[root]blast Lymphoblast Myeloblast Monoblast
t t
Polychromatop
pro[root]cyt Prolymphocyt Promegakaryo
hilic Promyelocyte Promonocyte
e e cyte
erythrocyte
Eosino/neutro/basophilic
[root]cyte - Normoblast Megakaryocyte
myelocyte
Eosinophilic/neutrophilic/ba
meta[root]c Large sophilic metamyelocyte, Early
Reticulocyte -
yte lymphocyte Eosinophilic/neutrophilic/ba monocyte
sophilic band cell
mature cell Small Erythrocyte granulocytes Monocyte thrombocytes
name lymphocyte (Eosino/neutro/basophil) (Platelets)

Osteoclasts also arise from haemopoietic cells of the monocyte/neutrophil lineage, specifically CFU-
GM.

Blood General Plasma - Hematopoietic stem cells

Lymphoid - WBC
T cells: Cytotoxic CD8+, Helper CD4+/Regulatory, γδ, Natural Killer T cell
B cells: Plasma, Memory
Natural killer cells (Lymphokine-activated killer cell)
Myeloid - WBC
Granulocytes (Neutrophil, Eosinophil, Basophil) - Mast cell precursors
Dendritic cells (Langerhans cells, Follicular dendritic cells)
Monocytes/Macrophages (Histiocytes, Kupffer cells, Langhans giant cells, Microglia, Osteoclasts)
Megakaryoblast - Megakaryocyte - Platelets
Myeloid - RBC Reticulocyte - Normoblast

T helper cell
(Redirected from T4 cells)

Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+
cells.

T helper cells (also known as effector T cells or Th cells) are a sub-group of lymphocytes (a type of
white blood cell or leukocyte) that plays an important role in establishing and maximizing the
capabilities of the immune system. These cells are unusual in that they have no cytotoxic or
phagocytic activity; they cannot kill infected host (also known as somatic) cells or pathogens, and
without other immune cells they would usually be considered useless against an infection. T h cells are
involved in activating and directing other immune cells, and are particularly important in the immune
system. They are essential in determining B cell antibody class switching, in the activation and growth
of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages. It is
this diversity in function and their role in influencing other cells that gives T helper cells their name.
Mature Th cells are believed to always express the surface protein CD4. T cells expressing CD4 are
also known as CD4+ T cells. CD4+ T cells are generally treated as having a pre-defined role as
helper T cells within the immune system, although there are known rare exceptions. For example,
there are sub-groups of suppressor T cells, natural killer T cells, and cytotoxic T cells that are known
to express CD4 (although cytotoxic examples have been observed in extremely low numbers in
specific disease states, they are usually considered non-existent). All of the latter CD4+ T cell groups
are not considered T helper cells, and are beyond the scope of this article.

The importance of helper T cells can be seen from HIV, a virus that infects cells that are CD4+
(including helper T cells). Towards the end of a HIV infection the number of functional CD4 + T cells
falls, which leads to the symptomatic stage of infection known as the acquired immune deficiency
syndrome (AIDS). There are also rare disorders, probably genetic in etiology, that result in the
absence or dysfunction of CD4+ T cells. These disorders produce similar symptoms, and many of
these are fatal (see T-Lymphocytopenia).

Major histocompatibility complex

From Wikipedia, the free encyclopedia

Protein images comparing the MHC I (1hsa) and MHC II (1dlh) molecules. (more details...)

The major histocompatibility complex (MHC) is a large genomic region or gene family found in
most vertebrates. It is the most gene-dense region of the mammalian genome and plays an important
role in the immune system, autoimmunity, and reproductive success. The proteins encoded by the
MHC are expressed on the surface of cells in all jawed vertebrates, and display both self antigens
(peptide fragments from the cell itself) and nonself antigens (e.g. fragments of invading
microorganisms) to a type of white blood cell called a T cell that has the capacity to kill or co-ordinate
the killing of pathogens, infected or malfunctioning cells.


Classification
In humans, the 3.6 Mb (3 600 000 base pairs) MHC region on chromosome 6 contains 140 genes
between flanking genetic markers MOG and COL11A2.[1] About half have known immunological
functions (see human leukocyte antigen). The same markers in the marsupial Monodelphis domestica
(gray short-tailed opossum) span 3.95 Mb and contain 114 genes, 87 shared with humans.[2]

[edit] Subgroups

The MHC region is divided into three subgroups called MHC class I, MHC class II, and MHC class III.

Name Function Expression

All nucleated cells. MHC class I proteins
Encodes heterodimeric peptide binding proteins, contain an a chain & b2-micro-globulin b
MHC
as well as antigen processing molecules such chain. They present antigen fragments to
class I
as TAP and Tapasin. cytotoxic T-cells cells and will bind to CD8
on cytotoxic T-cells.
Encodes heterodimeric peptide binding proteins On antigen-presenting cells MHC class II
and proteins that modulate peptide loading onto proteins contain a & b chains and they
MHC
MHC class II proteins in the lysosomal present antigen fragments to T-helper cells
class II
compartment such as MHC II DM, MHC II DQ, by binding to the CD4 receptor on the T-
MHC II DR and MHC II DP. helper cells.
Encodes for other immune components, such as
MHC
complement components (e.g., C2, C4, factor B)
class III Variable (see below)
and some that encode cytokines (e.g., TNF-α)
region
and also hsp.

Class III has a very different function than class I and II, but it has a locus between the other two (on
chromosome 6 in humans), so they are frequently discussed together.

Responses

The MHC proteins act as "signposts" that display fragmented pieces of an antigen on the host cell's
surface. These antigens may be self or nonself. If they are nonself, there are two ways by
which the foreign protein can be processed and recognized as being "nonself".

 If the host is a leukocyte, such as a monocyte or neutrophil, it may have engulfed the particle
(be it bacterial, viral, or particulate matter), broken it apart using lysozymes, and displayed the
fragments on Class II MHC molecules.

 On the other hand, if a host cell was infected by a bacterium or virus, or was cancerous, it may
have displayed the antigens on its surface with a Class I MHC molecule. In particular,
cancerous cells and cells infected by a virus have a tendency to display unusual, nonself
antigens on their surface. These nonself antigens, regardless of which type of MHC
molecule they are displayed on, will initiate the specific immunity of the host's body.
It is important to note that cells constantly process endogenous proteins and present them within the
context of MHC I. Immune effector cells are trained not to react to self peptides within MHC, and as
such are able to recognize when foreign peptides are being presented during an infection/cancer.

HLA genes
Main article: Human leukocyte antigen

The best-known genes in the MHC region are the subset that encodes cell-surface antigen-
presenting proteins. In humans, these genes are referred to as human leukocyte antigen (HLA)
genes, although people often use the abbreviation MHC to refer to HLA gene products. To clarify the
usage, some of the biomedical literature uses HLA to refer specifically to the HLA protein molecules
and reserves MHC for the region of the genome that encodes for this molecule; however this
convention is not consistently adhered to.

The most intensely-studied HLA genes are the nine so-called classical MHC genes: HLA-A, HLA-B,
HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. In humans, the
MHC is divided into three regions: Class I, II, and III. The A, B, and C genes belong to MHC class I,
whereas the six D genes belong to class II.

Besides being scrutinized by immunologists for its pivotal role in the immune system, the MHC has
also attracted the attention of many evolutionary biologists, due to the high levels of allelic diversity
found within many of its genes. Indeed, much theory has been devoted to explaining why this
particular region of the genome harbors so much diversity, especially in light of its immunological
importance.

Molecular biology of MHC proteins

The classical MHC molecules (also referred to as HLA molecules in humans) have a vital role in the
complex immunological dialogue that must occur between T cells and other cells of the body. At
maturity, MHC molecules are anchored in the cell membrane, where they display short polypeptides
to T cells, via the T cell receptors (TCRs). The polypeptides may be "self," that is, originating from a
protein created by the organism itself, or they may be foreign ("nonself"), originating from bacteria,
viruses, pollen, etc. The overarching design of the MHC-TCR interaction is that T cells should ignore
self peptides while reacting appropriately to the foreign peptides.

The immune system has another and equally important method for identifying an antigen: B cells with
their membrane-bound antibodies, also known as B cell receptors (BCRs). However, whereas the
BCRs of B cells can bind to antigens without much outside help, the TCRs of T cells require
"presentation" of the antigen: this is the job of MHC. It is important to realize that, during the vast
majority of the time, MHC are kept busy presenting self-peptides, which the T cells should
appropriately ignore. A full-force immune response usually requires the activation of B cells via BCRs
and T cells via the MHC-TCR interaction. This duplicity creates a system of "checks and balances"
and underscores the immune system's potential for running amok and causing harm to the body (see
autoimmune disorders).

All MHC molecules receive polypeptides from inside the cells they are part of and display them on the
cell's exterior surface for recognition by T cells. However, there are major differences between MHC
class I and MHC class II in the method and outcome of peptide presentation.
MHC evolution and allelic diversity
MHC gene families are found in essentially all vertebrates, though the gene composition and genomic
arrangement vary widely. Chickens, for instance, have one of the smallest known MHC regions (19
genes), though most mammals have an MHC structure and composition fairly similar to that of
humans. Gene duplication is almost certainly responsible for much of the genetic diversity. In
humans, the MHC is littered with many pseudogenes.

One of the most striking features of the MHC, particularly in humans, is the astounding allelic diversity
found therein, and especially among the nine classical genes. In humans, the most conspicuously-
diverse loci, HLA-A, HLA-B, and HLA-DRB1, have roughly 250, 500, and 300 known alleles
respectively -- diversity truly exceptional in the human genome. The MHC gene is the most
polymorphic in the genome. Population surveys of the other classical loci routinely find tens to a
hundred alleles -- still highly diverse. Many of these alleles are quite ancient: it is often the case that
an allele from a particular HLA gene is more closely related to an allele found in chimpanzees than it
is to another human allele from the same gene.

Phylogenetically the marsupial MHC lies between eutherian mammals and the minimal essential
MHC of birds, although it is closer in organization to non-mammals. Its Class I genes have amplified
within the Class II region, resulting in a unique Class I/II region.[2]

The allelic diversity of MHC genes has created fertile grounds for evolutionary biologists. The most
important task for theoreticians is to explain the evolutionary forces that have created and maintained
such diversity. Most explanations invoke balancing selection, a broad term that identifies any kind of
natural selection in which no single allele is absolutely most fit. Frequency-dependent selection and
heterozygote advantage are two types of balancing selection that have been suggested to explain
MHC allelic diversity. However, recent models suggest that a high number of alleles is not plausibly
achievable through heterozygote advantage alone. Pathogenic co-evolution, a counter-hypothesis
has recently emerged; it theorizes that the most common alleles will be placed under the greatest
pathogenic pressure, thus there will always be a tendency for the least common alleles to be
positively selected for. This creates a "moving target" for pathogen evolution. As the pathogenic
pressure decreases on the previously common alleles, their concentrations in the population will
stabilize, and they will usually not go extinct if the population is large enough, and a large number of
alleles will remain in the population as a whole. This explains the high degree of MHC polymorphism
found in the population, although an individual can have a maximum of 18 MHC I or II alleles.

MHC and sexual selection

It has been suggested that Claus Wedekind be merged into this article or section. (Discuss)

It has been suggested that MHC plays a role in the selection of potential mates, via olfaction. MHC
genes make molecules that enable the immune system to recognise invaders; generally, the more
diverse the MHC genes of the parents, the stronger the immune system of the offspring. It would
obviously be beneficial, therefore, to have evolved systems of recognizing individuals with different
MHC genes and preferentially selecting them to breed with.

Yamazaki et al. (1976) showed this to be the case for male mice, who show such a preference for
females of different MHC. Similar results have been obtained with fish. [3]
In 1995, Swiss biologist Claus Wedekind determined MHC-dissimiliar mate selection tendencies in
humans. In the experiment, a group of female college students smelled t-shirts that had been worn by
male students for two nights, without deodorant, cologne or scented soaps. Overwhelmingly, the
women preferred the odors of men with dissimilar MHCs to their own. However, their preference was
reversed if they were taking oral contraceptives. [4] The hypothesis is that MHCs affect mate choice
and that oral contraceptives can interfere with this. A study in 2005 on 58 test subects showed similar
results.[5]

Additional images

TCR-MHC bindings

Plasma cell
(Redirected from Plasma cells)

Plasma cells (also called plasma B cells or plasmocytes) are cells of the immune system that
secrete large amounts of antibodies. They differentiate from B cells upon stimulation by CD4+
lymphocytes. The B cell acts as an antigen presenting cell (APC), consuming an offending pathogen.
That pathogen gets taken up by the B cell by receptor mediated endocytosis, and broken down within
these endosomes after fusion with lysosomes releasing proteolytic enzymes onto the pathogen. Once
the enzymes break down the pathogen, pieces of the pathogen (which are now known as antigenic
peptides) are loaded onto MHC II molecules, and presented on its extracellular surface. Once on the
extracellular surface, the CD4+ T-helper lymphocyte will bind to the MHC II/Antigen molecule and
cause activation of the B cell, which includes differentiation into a plasma cell, and subsequent
generation of antibody against the consumed pathogen.
Overview
After dividing for around five days, mature B cells differentiate into either plasma B cells or memory B
cells. Most plasma B cells travel to the spleen or bone marrow to secrete antibodies (approximately
10,000 per second). During the initial stages of an immune response the lifespan of plasma cells is
very short, typically only a few days to weeks. However, following the process of affinity maturation,
plasma cells can survive for months to years and continue to secrete high levels of antibodies.
Memory B cells tend to be longer-lived and can therefore respond quickly upon second exposure to
an antigen.

The class of antibody that a plasma cell produces depends on signals, called cytokines, from other
immune system cells, such as macrophages and T helper cells. This process is called isotype-
switching. For example, plasma cells will likely secrete IgG3 antibodies if they matured in the
presence of the cytokine interferon-gamma. Since B cell maturation also involves somatic
hypermutation, these antibodies have a very high affinity for their antigen.

Microscopic anatomy
Plasma cells are large lymphocytes with a considerable nucleus-to-cytoplasm ratio and a
characteristic appearance on light microscopy. They have basophilic cytoplasm and an eccentric
nucleus with heterochromatin in a characteristic cartwheel arrangement. Their cytoplasm also
contains a pale zone that on electron microscopy contains an extensive Golgi apparatus and
centrioles. Abundant rough endoplasmic reticulum combined with a well-developed Golgi apparatus
makes plasma cells well-suited for secreting immunoglobulins.

Role in disease
Cancer of plasma cells is termed multiple myeloma. This condition is frequently identified because
malignant plasma cells continue producing an antibody, which can be detected as a paraprotein.

Common variable immunodeficiency is thought to be due to a problem in the differentiation from

lymphocytes to plasma cells. The result is a low serum antibody level and risk of infections.
Immunoglobulin G
From Wikipedia, the free encyclopedia

(Redirected from IgG)

Molecular surface of an IgG molecule

Immunoglobulin G (IgG) is a multimeric immunoglobulin, built of two heavy chains γ and two light
chains. Each complex has two antigen binding sites. This is the most abundant immunoglobulin and
is approximately equally distributed in blood and in tissue liquids, constituting 75% of serum
immunoglobulins in humans.[1]

 In birds, IgG is often called IgY, and is found in serum and yolk.[2]

Functions
This is the only isotype that can pass through the human placenta (except for IgG2[3]), thereby
providing protection to the fetus in its first weeks of life before its own immune system has developed.

It can bind to many kinds of pathogens, for example viruses, bacteria, and fungi, and protects the
body against them by complement activation (classic pathway), opsonization for phagocytosis and
neutralisation of their toxins.

IgG can cause food allergy, and in such causes delayed-onset food allergy, in contrast to food allergy
by IgE, whose effects appear rapidly.

Subclasses
Crosses placenta Complement Binds to Fc receptors on phagocytic
Name Percent
easily activator cells
IgG1 66% yes second highest high affinity
IgG2 23% no third highest extremely low affinity
IgG3 7% yes highest high affinity
IgG4 4% yes no intermediate affinity

Note: IgG affinity to Fc receptors on phagocytic cells is specific to individual species from which the
antibody comes as well as the class.
Immunoglobulin M
From Wikipedia, the free encyclopedia

(Redirected from IgM)

IgM (Immunoglobulin M) antibody molecule consisting of 5 base units.

1: Base unit.
2: Heavy chains.
3: Light chains.
4: J chain.
5: Intermolecular disulfide bonds.

IgM scheme. Heavy chains are blue; light chains are yellow.
 Immunoglobulin M, or IgM for short, is a basic antibody that is present on B cells. It is the
primary antibody against A and B antigens on red blood cells. IgM is by far the physically
largest antibody in the human circulatory system.

Structure and function

IgM forms polymers where multiple immunoglobulins are covalently linked together with disulfide
bonds, mostly as a pentamer but also as a hexamer. IgM has a molecular mass of approximately 900
kD (in its pentamer form). Because each monomer has two antigen binding sites, a pentameric IgM
has 10 binding sites. Typically, however, IgM cannot bind 10 antigens at the same time because the
large size of most antigens hinders binding to nearby sites.

The J chain is found in pentameric IgM but not in the hexameric form, perhaps due to space
constraints in the hexameric complex. Pentameric IgM can also be made in the absence of J chain.
At present, it is still uncertain what fraction of normal pentamer contains J chain, and to this extent it
is also uncertain whether a J chain-containing pentamer contains one or more than one J chain. [1]
Because IgM is a large molecule, it cannot diffuse well, and is found in the interstitium only in very low
quantities. IgM is primarily found in serum; however, because of the J chain, it is also important as a
secretory immunoglobulin.

Due to its polymeric nature, IgM possesses high avidity, and is particularly effective at complement
activation.

Expression
In germline cells, the gene segment encoding the μ constant region of the heavy chain is positioned
first among other constant region gene segments. For this reason, IgM is the first immunoglobulin
expressed by mature B cells.

It is also the first immunoglobulin expressed in the fetus (around 20 weeks) and also phylogenetically
the earliest antibody to develop.[2]

Clinical significance
IgM antibodies appear early in the course of an infection and usually do not reappear after further
exposure. IgM antibodies do not pass across the human placenta.

These two biological properties of IgM make it useful in the diagnosis of infectious diseases.
Demonstrating IgM antibodies in a patient's serum indicates recent infection, or in a neonate's serum
indicates intrauterine infection (e.g. congenital rubella).

Other points
IgM in normal serum is often found to bind to specific antigens, even in the absence of prior
immunization. For this reason IgM has sometimes been called a "natural antibody". This phenomenon
is probably due to the high avidity of IgM that allow it to bind detectably even to weakly cross-reacting
antigens that are naturally occurring in nature. For example the IgM antibodies that bind to the red
blood cell A and B antigens might be formed in early life as a result of exposure to A- and B-like
substances that are present on bacteria or perhaps also on plant materials.

IgM antibodies are mainly responsible for the clumping (agglutination) of red blood cells if the
recipient of a blood transfusion receives blood that is not compatible with his/her blood type.
Immunoglobulin A
(Redirected from IgA)

The dimeric IgA molecule. 1 H-chain, 2 L-chain, 3 J-chain, 4 secretory component

Ig A

Immunoglobulin A (IgA) is an antibody and, in its secretory form, is the main immunoglobulin found
in mucous secretions, including tears, saliva, colostrum, intestinal juice, vaginal fluid and secretions
from the prostate and respiratory epithelium. It is also found in small amounts in blood. Because it is
resistant to degradation by enzymes, secretory IgA can survive in harsh environments such as the
digestive and respiratory tracts, to provide protection against microbes that multiply in body
secretions.[1]

 IgA is a poor activator of the complement system, and opsonises only weakly. Its heavy chains
are of the type α.

Forms
IgA1 vs. IgA2

It exists in two isotypes, IgA1 (90%) and IgA2 (10%):

 IgA1 is found in serum and made by bone marrow B cells.

 In IgA2, the heavy and light chains are not linked with disulfide but with noncovalent bonds.
IgA2 is made by B cells located in the mucosae and has been found to secrete into colostrum,
maternal milk, tears and saliva.

Serum vs. secretory IgA

It is also possible to distinguish forms of IgA based upon their location - serum IgA vs. secretory IgA.

IgA is found in secretions in a specific form called secretory IgA', polymers of 2-4 IgA monomers
linked by two additional chains. One of these is the J chain (joining chain), which is a polypeptide of
molecular mass 1.5 kD, rich with cysteine and structurally completely different from other
immunoglobulin chains. This chain is formed in the IgA-secreting cells.
The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much
larger molecular mass (70 kD) called the secretory component that is produced by epithelial cells.
This molecule originates from the poly-Ig receptor (130 kD) that is responsible for the uptake and
transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into
secretions such as tears, saliva, sweat and gut fluid.

IgA activity
The high prevalence of IgA in mucosal areas is a result of a cooperation between plasma cells that
produce polymeric IgA (pIgA), and mucosal epithelial cells that express the an immunoglobulin
receptor called the polymeric Ig receptor (pIgR). pIgA is released from the nearby activated plasma
cells and binds to pIgR. This results in transportation of IgA across mucosal epithelial cells and its
cleavage from pIgR for release into external secretions.[2]

In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89), which is expressed on immune
effector cells, to initiate inflammatory reactions.[2] Ligation of FcαRI by IgA containing immune
complexes causes antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation of
eosinophils and basophils, phagocytosis by monocytes, macrophages, neutrophils and eosinophils,
and triggering of respiratory burst activity by polymorphonuclear leukocytes.[2]

Transport
Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent
to mucosal surfaces. It binds to the polymeric immunoglobulin receptor on the basolateral surface of
epithelial cells and is taken up into the cell via endocytosis. The receptor-IgA complex passes through
the cellular compartments before being secreted on the luminal surface of the epithelial cells, still
attached to the receptor. Proteolysis of the receptor occurs and the dimeric IgA molecule, along with
a portion of the receptor known as the secretory component, are free to diffuse throughout the
lumen.[3] In the gut, it can bind to the mucus layer on top of the epithelial cells to form a barrier
capable of neutralizing threats before they reach the cells.

Pathology
Decreased or absent IgA, termed selective IgA deficiency, can be a clinically significant
immunodeficiency.

Globulin
From Wikipedia, the free encyclopedia

Globulin is one of the two types of serum proteins, the other being albumin. This generic term
encompasses a heterogeneous series of families of proteins, with larger molecules and less soluble
in pure water than albumin, which migrate less than albumin during serum electrophoresis.

It is sometimes used synonymously with Globular protein. However, albumin is also a globular
protein, but not a globulin. All other serum globular proteins are globulins.
Protein electrophoresis is used to categorize globulins into the following four categories:

 Alpha 1 globulins
 Alpha 2 globulins
 Beta globulins
 Gamma globulins (one group of gamma globulins are immunoglobulins, that function as
antibodies)

Alpha globulin
(Redirected from Alpha 1 globulins)

Schematic representation of a protein electrophoresis gel

Alpha Globulins are a group of globular proteins in plasma, which are highly mobile in alkaline or
electrically charged solutions. They inhibit certain blood protease and inhibitor activity.

Examples
Alpha 1 globulins

a1-antitrypsin

Alpha 2 globulins

 haptoglobin
 a2-macroglobulin
 ceruloplasmin
Beta globulins

Schematic representation of a protein electrophoresis gel

Beta globulins are a group of globular proteins in plasma that are more mobile in alkaline or
electricaly charged solutions than gamma globulins, but less mobile than alpha globulins.

Examples of beta globulins include:

 beta-2 microglobulin
 plasminogen
 angiostatins
 properdin
 sex hormone-binding globulin
 transferrin

Oxygen-haemoglobin dissociation curve

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The O2-Hb dissociation curve is a sigmoidal curve that represents the relationship between O 2
concentration and the percentage saturation of Hb. As the concentration increases from about 90%
there is a significant plateau in the curve, which has several important biological repercussions.

The oxygen-haemoglobin dissociation curve plots the proportion of haemoglobin in its saturated
form on the vertical axis against the prevailing oxygen tension on the horizontal axis.

Sigmoidal shape
It is usually a sigmoid plot. A hemoglobin molecule can bind up to four oxygen molecules in a
reversible way.

The shape of the curve results from the interaction of bound oxygen molecules with incoming
molecules. The binding of the first molecule is difficult. However, this facilitates the binding of the
second and third molecules, and it is only when the fourth molecule is to be bound that the difficulty
increases, partly as a result of crowding of the hemoglobin molecule, partly as a natural tendency of
oxygen to dissociate.

The 'plateau' portion of the oxyhemoglobin dissociation curve is the range that exists at the
pulmonary capillaries (minimal reduction of oxygen transported until the p(O2) falls below 60 mmHg).

The 'steep' portion of the oxyhemoglobin dissociation curve is the range that exists at the systemic
capillaries (a small drop in systemic capillary p(O2) can result in the release of large amounts of
oxygen for the metabolically active cells).

Factors shifting curve

Many factors influence the affinity of this binding and alter the shape of the curve:

right shift left shift

temperature high low
DPG high low
p(CO2) high low
p(CO) low high
pH (Bohr effect) low (acidosis) high (alkalosis)
type of hemoglobin adult hemoglobin fetal hemoglobin

Left shift of the curve is a sign of hemoglobin's increased affinity for oxygen (eg. at the lungs).
Similarly, right shift shows decreased affinity, as would appear with an increase in body temperature,
hydrogen ion, 2,3-diphosphoglycerate or carbon dioxide concentration (the Bohr effect)

Carbon monoxide has a much higher affinity for haemoglobin than oxygen does. In carbon monoxide
poisoning, oxygen cannot be transported and released to body tissues thus resulting in hypoxia.

With fetal hemoglobin, the shift facilitates diffusion of oxygen across the placenta. The oxygen
dissociation curve for myoglobin exists even further to the left.
Red blood cell distribution width
(Redirected from RDW)

Human red blood cells

The red blood cell distribution width, or RDW, is a measure of the variation of red blood cell width
that is reported as part of a standard complete blood count. Usually red blood cells are a standard
size. Certain disorders, however, cause a significant variation in cell size. Higher RDW values
indicate greater variation in size. Normal range in human red blood cells is 11 - 15%. If anemia is
observed, RDW test results are often used together with MCV results to figure out what the cause of
the anemia might be. It is mainly used to differentiate between iron deficiency anemia, in which RDW
is elevated, and other microcytic anemias. It may denote hereditary spherocytosis. An elevated RDW,
i.e. red blood cells of unequal sizes, is known as anisocytosis.

Mathematically the RDW is calculated with the following formula:

RDW = (Standard deviation of red cell width ÷ mean cell width) × 100

Megaloblastic anemia
Megaloblastic anemia
Classification & external resources

Image:Megaloblastic anemia.jpg
Megaloblastic anemia blood smear
ICD-10 D51.1, D52.0, D53.1
ICD-9 281
DiseasesDB 29507
eMedicine med/1420 ped/2575
MeSH D000749

Megaloblastic anemia is an anemia (of macrocytic classification) which results from a deficiency of
vitamin B12 and folic acid. It can be the result of a lack of intrinsic factor.

It is characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the
bone marrow; associated with pernicious anemia
Causes
 nutritional defects (folic acid or vitamin B12 which is mainly from animal sources; vegans may
require supplementation)
 chronic liver diseases
 alcoholism
 pregnancy
 decreased production of intrinsic factor (this disease entity is called pernicious anemia)
 intestinal malabsorption (due to an enteritis, celiac disease or other causes).
 fish tapeworm infestation (Diphyllobothrium latum)
 failure to replicate chromosomes due to lack of thymidine.
 Lesch-Nyhan Syndrome
 cytotoxic drugs interfering with DNA synthesis
 intestinal flora disruption due to antibiotic use

Hematological findings
The blood film can point towards vitamin deficiency:

 Decreased red blood cell (RBC) count and hemoglobin levels

 Increased mean corpuscular volume (MCV, >95 fl) and mean corpuscular hemoglobin (MCH)
 The reticulocyte count is normal
 The platelet count may be reduced.
 Neutrophil granulocytes may show multisegmented nuclei ("senile neutrophil"). This is thought
to be due to decreased production and a compensatory prolonged lifespan for circulating
neutrophils.
 Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
 Macrocytes (larger than normal RBCs) are present.
 Ovalocytes (oval shaped RBCs) are present.
 Bone marrow (not normally checked in a patient suspected of megaloblastic anemia) shows
megaloblastic hyperplasia.
 Howell-Jolly bodies (chromosomal remnant) also present.

Blood chemistries will also show:

 Increased homocysteine and methylmalonic acid in B12 deficiency

 Increased homocysteine in folate defiency

Analysis
The Schilling test was performed in the past to determine the nature of the vitamin B12 deficiency, but
due to the lack of available radioactive B12, it is now largely a historical artifact. Vitamin B 12 is a
necessary prosthetic group to the enzyme methylmalonyl-coenzyme A mutase. B12 deficiency leads to
dysfunction of this enzyme and a buildup of its substrate, methylmalonic acid, the elevated level of
which can be detected in the urine and blood. Since the level of methylmalonic acid is not elevated in
folic acid deficiency, this test provides a reliable tool in differentiating the two.
Pathology: hematology (primarily C81-C96/200-208, D45-D47, D50-D77/280-289)
hematological malignancy (Lymphoma, leukemia)
WBCs -cytosis (Agranulocytosis, Leukocytosis, Lymphocytosis, Monocytosis) • -penia
(Lymphopenia, Neutropenia)
nutritional anemia: Iron deficiency anemia, Plummer-Vinson syndrome,
Megaloblastic anemia (Pernicious anemia)
hereditary hemolytic anemia: G6PD Deficiency, Thalassemia, Sickle-cell
disease/trait, Hereditary spherocytosis, Hereditary elliptocytosis, Hereditary
RBCs/anemia/
stomatocytosis
hemoglobinopathy
acquired hemolytic anemia: Warm autoimmune hemolytic anemia, HUS, MAHA,
PNH
aplastic anemia: Acquired PRCA, Diamond-Blackfan anemia, Fanconi anemia •
Sideroblastic anemia • Hemochromatosis
coagulopathy: DIC • Hemophilia (A, B, C, XIII) • Von Willebrand disease
Purpura: Henoch-Schönlein, ITP, TTP
primary hypercoagulable state: Protein C deficiency - Protein S deficiency -
Coagulation/platelets
Antithrombin III deficiency
other hemorrhagic conditions: Bernard-Soulier syndrome - Glanzmann's
thrombasthenia - Grey platelet syndrome
WHO-I Langerhans cell histiocytosis - non-Langerhans-cell histiocytosis/WHO-II
(Juvenile xanthogranuloma, Hemophagocytic lymphohistiocytosis) - malignant
Histiocytosis
histiocytic disorders/WHO-III (Acute monocytic leukemia, Malignant
histiocytosis, Erdheim-Chester disease)
Other Asplenia/hyposplenism - Methemoglobinemia

Reticulocyte
(Redirected from Reticulocytes)

Reticulocyte

Erythrocyte

Reticulocytes are immature red blood cells, typically composing about 1% of the red cells in the
human body. Reticulocytes develop and mature in the red bone marrow and then circulate for about a
day in the blood stream before developing into mature red blood cells. Like mature red blood cells,
reticulocytes do not have a cell nucleus. They are called reticulocytes because of a reticular (mesh-
like) network of ribosomal RNA that becomes visible under a microscope with certain stains such as
new methylene blue.

Reticulocytes appear slightly bluer than other red cells when looked at with the normal Romanowsky
stain. Reticulocytes are also slightly larger, which can be picked up as a high MCV (mean corpuscular
volume) with a full blood count done by a trained medical scientist, who has specialised in
haematology, or a machine.
 

Reticulocyte count
The reticulocyte count is the percentage of circulating red blood cells that are in the reticulocyte
stage.

To accurately measure reticulocyte counts, automated counters that use lasers mark cell samples
with fluorescent dye that marks RNA and DNA (such as thiazole orange).[1] This distinguishes
reticulocytes as the middle ground of dye response to laser light, between red blood cells (which have
neither RNA nor DNA) and lymphocytes (which have a large amount of DNA, unlike reticulocytes).[2]

The normal range of values for reticulocytes in the blood depends on the clinical situation and the lab,
but broadly speaking is 0.5% to 1.5%. However, if a person has anaemia, their reticulocyte
percentage should be higher than "normal" if the bone marrow to produce new blood cells remains
intact. Thus, calculating the reticulocyte production index is an important step in understanding
whether the reticulocyte count is appropriate or inappropriate to the situation. This is often a more
important question than whether the percentage is in the normal range; for instance, if someone is
anemic but only has a reticulocyte percentage of 1%, this means that the bone marrow is likely not
producing new blood cells at a rate that will correct the anemia. The number of reticulocytes is a good
indicator of bone marrow activity, because it represents recent production. This means that the
reticulocyte count, and the reticulocyte production index that can be calculated from it, can be used to
determine whether a production problem is contributing to the anaemia, and can also be used to
monitor the progress of treatment for anaemia.

The specimen requirement for a reticulocyte count is EDTA anti-coagulated whole blood (lavender-
top bottle if using the Vacutainer®, Vacuette® or Monoject® systems; red-top if using the S-
Monovette® system).

When there is an increased production of red blood cells to overcome chronic or severe loss of
mature red blood cells, such as in a haemolytic anaemia, people often have a markedly high number
and percentage of reticulocytes. A very high number of reticulocytes in the blood can be described as
reticulocytosis.

Abnormally low numbers of reticulocytes can be attributed to chemotherapy, aplastic anaemia,

pernicious anaemia, bone marrow malignancies, problems of erythropoietin production, or other
causes of anaemia due to poor RBC production.
Coagulation factors
Coagulation factors and related substances
Number and/or name Function
I (fibrinogen) Forms clot (fibrin)
II (prothrombin) Its active form (IIa) activates I, V, VII, XIII, protein C, platelets
Tissue factor Co-factor of VIIa (formerly known as factor III)
Required for coagulation factors to bind to phospholipid (formerly
Calcium
known as factor IV)
V (proaccelerin, labile factor) Co-factor of X with which it forms the prothrombinase complex
VI Unassigned – old name of Factor Va
VII (stable factor) Activates IX, X
VIII (antihemophilic factor) Co-factor of IX with which it forms the tenase complex
IX (Christmas factor) Activates X: forms tenase complex with factor VIII
X (Stuart-Prower factor) Activates II: forms prothrombinase complex with factor V
XI (plasma thromboplastin
Activates XII, IX and prekallikrein
antecedent)
XII (Hageman factor) Activates prekallikrein and fibrinolysis
XIII (fibrin-stabilizing factor) Crosslinks fibrin
von Willebrand factor Binds to VIII, mediates platelet adhesion
prekallikrein Activates XII and prekallikrein; cleaves HMWK
high molecular weight kininogen
Supports reciprocal activation of XII, XI, and prekallikrein
(HMWK)
fibronectin Mediates cell adhesion
antithrombin III Inhibits IIa, Xa, and other proteases;
Inhibits IIa, cofactor for heparin and dermatan sulfate ("minor
heparin cofactor II
antithrombin")
protein C Inactivates Va and VIIIa
Cofactor for activated protein C (APC, inactive when bound to C4b-
protein S
binding protein)
Mediates thrombin adhesion to phospholipids and stimulates
protein Z
degradation of factor X by ZPI
Protein Z-related protease Degrades factors X (in presence of protein Z) and XI
inhibitor (ZPI) (independently)
plasminogen Converts to plasmin, lyses fibrin and other proteins
alpha 2-antiplasmin Inhibits plasmin
tissue plasminogen activator
Activates plasminogen
(tPA)
urokinase Activates plasminogen
plasminogen activator inhibitor-1
Inactivates tPA & urokinase (endothelial PAI)
(PAI1)
plasminogen activator inhibitor-2
Inactivates tPA & urokinase (placental PAI)
(PAI2)
cancer procoagulant Pathological factor X activator linked to thrombosis in cancer
[edit] History
[edit] Initial discoveries

Theories on the coagulation of blood have existed since antiquity. Physiologist Johannes Müller
(1801-1858) described fibrin, the substance of a thrombus. Its soluble precursor, fibrinogen, was thus
named by Rudolf Virchow (1821-1902), and isolated chemically by Prosper Sylvain Denis (1799-
1863). Arthus discovered in 1890 that calcium was essential in coagulation.[2] Alexander Schmidt
suggested that the conversion from fibrinogen to fibrin was the result of an enzymatic process, and
labeled the hypothetical enzyme "thrombin" and its precursor "prothrombin".[3][4] Platelets were
identified in 1865, and their function was elucidated by Giulio Bizzozero in 1882.[5]

The theory that thrombin was generated by the presence of tissue factor was consolidated by Paul
Morawitz in 1905.[6] At this stage, it was known that thrombokinase/thromboplastin (factor III) was
released by damaged tissues, reacting with prothrombin (II), which, together with calcium (IV), formed
thrombin, which converted fibrinogen into fibrin (I).[7]

[edit] Coagulation factors

The remainder of the biochemical factors in the process of coagulation were largely discovered in the
20th century.

A first clue as to the actual complexity of the system of coagulation was the discovery of proaccelerin
(initially and later called Factor V) by Paul Owren (1905-1990) in 1947. He also postulated that its
function was the generation of accelerin (Factor VI), which later turned out to be the activated form of
V (or Va); hence, VI is not now in active use.[7]

Factor VII (also known as serum prothrombin conversion accelerator or proconvertin, precipitated by
barium sulfate) was discovered in a young female patient in 1949 and 1951 by different groups.

Factor VIII turned out to be deficient in the clinically recognised but etiologically elusive hemophilia A;
it was identified in the 1950s and is alternatively called antihemophilic globulin due to its capability to
correct hemophilia A.[7]

Factor IX was discovered in 1952 in a young patient with hemophilia B named Stephen Christmas
(1947-1993). His deficiency was described by Dr. Rosemary Biggs and Professor R.G. MacFarlane in
Oxford, UK. The factor is hence called Christmas Factor or Christmas Eve Factor. Christmas lived in
Canada, and campaigned for blood transfusion safety until succumbing to transfusion-related AIDS at
age 46. An alternative name for the factor is plasma thromboplastin component, given by an
independent group in California.[7]

Hageman factor, now known as factor XII, was identified in 1955 in an asymptomatic patient with a
prolonged bleeding time named of John Hageman. Factor X, or Stuart-Prower factor, followed, in
1956. This protein was identified in a Ms. Audrey Prower of London, who had a lifelong bleeding
tendency. In 1957, an American group identified the same factor in a Mr. Rufus Stuart. Factors XI and
XIII were identified in 1953 and 1961, respectively.[7]

[edit] Nomenclature

The usage of Roman numerals rather than eponyms or systematic names was agreed upon during
annual conferences (starting in 1955) of hemostasis experts. This committee evolved into the
present-day International Committee on Thrombosis and Hemostasis (ICTH). Assignment of
numerals ceased in 1963 after the naming of Factor XIII. The names Fletcher Factor and Fitzgerald
Factor were given to further coagulation-related proteins, namely prekallikrein and high molecular
weight kininogen respectively.[7]

Factors III and VI are unassigned, as thromboplastin was never identified, and actually turned out to
consist of ten further factors, and accelerin was found to be activated Factor V.