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T cell maturation, activation anddifferentiation
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Activates immune and inflammatory response lymphokine It expresses different membrane molecules:
Thy-1: earliest marker of T cell lineage, remains
throughout life TCR: present on all cells; two polypeptide chain
CD3: six polypeptide chain complex associated withTCR
CD4 or CD8: CD4 on TH cells; CD8 on TC cells CD28: ligand for co stimullatory B7 molecules present
on APC
CD45: participate in signal transductions
T lymphocytes
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After the naive T cell (N) encounters
an antigen - proliferate (divide) into many
clones or daughter cells.
Some will differentiate into effectors T cells(E) that will produce cytokines
Some will form memory T cells (M) that
will survive in an inactive state
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T lymphocytes
Differ from B cell and NK cell by having TCR
Earliest thymocytes express neither CD4 nor CD8, and are
therefore classed as double-negative(CD4-CD8-) cells
Double negative double positive single positive
released from the thymus to peripheral tissues.
About 98% of thymocytes die during the development
processes in the thymus
Either by failing positive selection or negative selection,
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Positive selection
"selects for" T-cells capable of interacting with MHC Double-positive thymocytes (CD4+/CD8+) move deep into the
thymic cortex where they are presented with self-antigenscomplexed with MHC molecules on the surface ofcortical epithelial cells.
Only those thymocytes that bind the MHC/antigen complexwith adequate affinity will receive a vital "survival signal.
Because of this, the thymocytes with no affinity for self antigensdie by apoptosis and are engulfed by macrophages.
Double-positive cells (CD4+/CD8+) that are positively selectedon MHC class II molecules will eventually become CD4+ cells,while cells positively selected on MHC class I molecules matureinto CD8+ cells.
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Negative selection Removes thymocytes that are capable of strongly binding with
"self" peptides presented by MHC. Remove thymocytes that may cause autoimmunity
Thymocytes that survive positive selection migrate towards theboundary of the thymic cortex and thymic medulla.
While in the medulla, they are again presented with self-antigen in complex with MHC molecules on antigen-presenting cells (APCs) such as dendritic cells andmacrophages.
Thymocytes that interact too strongly with the antigen receivean apoptotic signal that leads to cell death.
Positive selection selects for T cells that are capable ofrecognizing self antigens through MHC. Negative selectionselects for T cells that bind too strongly to self antigens.
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T cell receptors (TCR) Responsible for recognizing antigens bound to MHC
Binding between TCR and antigen is of relatively low affinity andis degenerate
Heterodimer; in 95% of T cells contains alpha () and beta ()fragment, whereas in 5% of T cells has gamma and delta (/)fragment
Transmembrane region of the TCR is composed of positivelycharged amino acids; such structure allows the TCR to associate withother molecules like CD3, which possess three distinct chains (, ,and ) or 2 complex or a / complex
These accessory molecules have negatively charged transmembraneregions and are vital to propagating the signal from the TCR into thecell;
The cytoplasmic tail of the TCR is extremely short, making it unlikely
to participate in signaling.
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Helper T cell (TH Cells) Assist other white blood cells in immunologic processes
They have no cytotoxic or phagocytic activity; they cannot killinfected host cells or pathogens
They are essential in determining B cell antibody classswitching, in the activation and growth of cytotoxic T cells, andin maximizing bactericidal activity of phagocytes such asmacrophages.
For proliferation they need IL2, secreted by itself (autocrine) they express the T cell receptor-CD3 complexS
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After many cell generations, the Th cell's progenitorsdifferentiate into effector Th cells, memory Th cells,and regulatory Th cells.
Effector Th cells secrete cytokines, proteins or peptides thatstimulate or interact with other leukocytes, including Thcells.
Memory Th cells retain the antigen affinity of the originallyactivated T cell, and are used to act as later effector cells during a
second immune response (e.g. if there is re-infection of the host ata later stage).
Regulatory T cells do not promote immune function, but act todecrease it instead. Despite their low numbers during aninfection, these cells are believed to play an important role in theself-limitation of the immune system; they have been shown toprevent the development of various auto-immune diseases.
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T-Killer cell, cytolytic T cell, CD8+ T-cells or killer T cell)
Inducing the death of infected somatic or tumor cells Virus-infected cells (e.G., HIV-infected CD4+ T cells); Cells infected with intracellular bacterial or protozoal parasites; Allograft such as transplanted kidney, heart, lungs, etc.
Two types of killing Perforin/Granzyme Killing perforin molecules insert themselves into the plasma membrane
of target cells forming a pore that enables Granzymes are serine proteases. The two most abundant ones
are-- Granzyme A. Once inside the cell, it cleaves a subunit ofcomplex I (the NADH dehydrogenase) of the ETC producing ROSthat kill the cell.
Granzyme B. Once inside the cell, it proceeds to cleave theprecursors ofcaspases thus activating them to cause the cell toself-destruct by apoptosis.
Cytotoxic T cell (Tc Cells)
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FasL/Fas Killing Express on their surface molecules of a transmembrane protein,
the death activator designated Fas ligand (FasL) (Apo1L)(CD95L)
Most potential CTL targets express a receptor for FasLdesignated Fas (Apo1)(CD95) When cytotoxic T cells recognize (bind to) their target,
they produce more FasL at their surface.
This binds with the Fas on the surface of the target cell leadingto its death by apoptosis.
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Types Central memory TCM cells express L-selectin (CD62L)
and the CCR7, they secrete IL-2, but not IFN or IL-4.
Effector memory TEM cells, however, do not express L-selectin or CCR7 but produce effector cytokines likeIFN and IL-4.
Explored using co-stimulatory molecules CD27 andCD28 expression in addition to CCR7 and CD62L
Memory T cell (TM Cells)
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Natural Killer T cells Share properties of both T cells and natural killer (NK) cells Bridges between innate between adaptive immunity,
Co-express an T cell receptor (TCR), but also express a varietyof molecular markers that are typically associated with NK cells,such as NK1.1.
Share other features with NK cells as well, such as CD16 andCD56 expression and granzyme production.
Unlike conventional T cells that recognize peptide antigenpresented by MHC molecules, NKT cells recognize glycolipidantigen presented by a molecule called CD1d,
They are also able to recognize and eliminate some tumor cellsand cells infected with herpes viruses,
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Once activated, these cells can perform functions ascribed to bothTH and TC cells (i.e., cytokine production and release ofcytolytic/cell killing molecules),
Upon activation, NKT cells are able to produce large quantities
of interferon-gamma, IL-4, and granulocyte-macrophage colony-stimulating factor, as well as multiple other cytokines andchemokines (such as IL-2, Interleukin-13, Interleukin-17,Interleukin-21 and TNF-alpha).
S i li d i i ll i il d d i i
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Specialised antigen presenting cells are primarily dendriticcells, macrophages and B cells, although B cells are theonly cell group that expresses MHC Class II constitutively
(at all times). Some APCs also bind native (or unprocessed) antigens to
their surface, such as follicular dendritic cells, butunprocessed antigens do not interact with T cells and are
not involved in their activation. The antigens that bind to MHC proteins are always
short peptides, 8-10 amino acids long for MHC Class I,
and up to 25 or so for MHC Class II.
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Signal 1 of T cell activationEndocytose (absorb) foreign material, which undergoes processing,
then travels from the infection site to the lymph nodes.
APC begins to present antigen peptides with Class II MHC, allowingCD4+ T cells that express the specific TCRs.
TCR-CD3 complex binds strongly to the peptide-MHC complex. CD4,also binds to a different section of the MHC molecule.
These interactions bring these proteins closer together, allowing the
intracellular kinases present on the TCR, CD3 and CD4 proteins toactivate each other via phosphorylation.
With the assistance of a phosphatase present on the intracellularsection of CD45 (common leukocyte antigen), these molecules
activate the major biochemical pathways in the cytosol of the Th cell.
Th i t i t i LFA 1 th T ll d ICAM th APC
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The integrin protein LFA-1 on the T cell and ICAM on the APC arethe primary molecules of adhesion in this cell interaction.Verification (Signal 2)
Involves an interaction between CD28 on the CD4+ T cell andthe proteins CD80 (B7.1) or CD86 (B7.2) on the professionalAPCs. Both CD80 and CD86 activate the CD28 receptor.
Once the two-signal activation is complete the T helper cell (Th)
then allows itself to proliferate by releasing a potent T cellgrowth factor called interleukin 2 (IL-2) which acts inan autocrine fashion.
Activated T cells also produce the alpha sub-unit of the IL-2
receptor (CD25 or IL-2R. The Th cells receiving both signals of activation will then
become Th0 cells (T helper 0) cell that secrete IL-2, IL-4 and interferon gamma (IFN-).
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The Th0 cells will then differentiate into Th1 or Th2 cells depending
on cytokine environment.
IFN- drives Th1 cell production while IL-10 and IL-4 inhibit Th1 cell
production. Conversely, IL-4 drives Th2 cell production and IFN-inhibits Th2 cells.
TheTh0 cells are nave T cells thatproduce cytokines typical of both Th1
and Th2 cells. In general,Th1cellsproduce lymphokines that stimulatemacrophages and cytotoxic TcellswhilstTh2 cells produce lymphokinesthat stimulate B cells to proliferateand produce antibody. In contrast,Th3 cells produce cytokines that areinvolved in the regulation orswitching off of the immune
response.
Th1 Th2
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Th1 Th2
Main partner cells Macrophage B cells
Cytokines produced IFN-, TNF IL4, IL5, IL6, IL10, IL13
Immune stimulation
promoted
Cellular immune
system. Maximizes
the killing efficacy of
the macrophages
Humoral immune system.
Stimulates B-cells into
proliferation, to induce B-
cell antibody classswitching.
Other function Increases the
production
of interleukin-12 bydendritic cells and
macrophages.
IL4 acts on helper T cells
to promote the
production of Th2cytokines whileIL-10
inhibits IL2 and IFN- in
helper T cells and IL-12 in
dendritic cells and
macrophages.
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B cells B cells are produced in the bone marrow.
have immunoglobulin and other molecules (e.g. CD19, 20,23, 24, 35 and 40) inserted in their membranes.
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BCR Transmembrane receptor protein located on the outer
surface of B-cells In addition to Immunoglobulin (mIg), the BCR comprises a
duplex of molecules known as CD79a/b (formerly Ig andIg) that have a single extracellular region and acytoplasmic tail.
The B-cell receptor is composed of two parts
Ligand binding moiety
Signal transduction moiety: heterodimer called Ig-/Ig- (CD7.Each member of the dimer spans the plasma membrane and has a
cytoplasmic tail bearing an immunoreceptor tyrosine-based
activation motif (ITAM))
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BCR and TCR Both BCRs and TCRs share these properties:
They are integral membrane proteins.
They are present in thousands of identical copies exposed atthe cell surface.
They are made before the cell ever encounters an antigen.
They are encoded by genes assembled by the recombinationof segments of DNA.
They have a unique binding site.
This site binds to a portion of the antigen called an antigenicdeterminant or epitope.
The binding, like that between an enzyme and its substratedepends on complementarity of the surface of the receptorand the surface of the epitope.
The binding occurs by non-covalent forces (again, like anenzyme binding to its substrate).
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BCRs and TCRs differ in:
Their structure;
The genes that encode them;
The type of epitope to which they bind.
h b l l
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Major histocompatibility complex MHC complex is group of genes on a single chromosome
that codes the MHC antigens
MHC molecules play an important role in the immunesystem and autoimmunity.
MHC genes present proteins through several mechanisms:
the MHC locus is polygenic,
MHC genes are highly polymorphic and numerous alleles have
been described, and
several MHC genes are codominantly expressed.
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MHC1
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MHC1 Composed of two polypeptide chains, a long chain and a
short chain called 2-microglobulin
The chain has four regions. A cytoplasmic region, containing sites for phosphoylation and
binding to cytoskeletal elements.
A transmembrane region containing hydrophic amino acids bywhich the molecule is anchored in the cell membrane.
A highly conserved 3 immunoglubilin-like domain to whichCD8 binds.
A highly polymorphic peptide binding region formed from the 1and 2 domains.
The 2- microglobulin associates with the chain andhelps maintain the proper conformation of the molecule.
MHC2
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MHC2Class II MHC molecules are composed of two polypeptide
chains an and a chain of approximately equal length.Both chains have four regions:
A cytoplasmic region containing sites for phosphoylation and
binding to cytoskeletal elements
A transmembrane region containing hydrophic amino acids by
which the molecule is anchored in the cell membrane
A highly conserved 2 domain and a highly conserved 2 domain
to which CD4 binds
A highly polymorphic peptide binding region formed from the 1
and 1 domains
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Each MHC molecule has only one binding site. The different peptides agiven MHC molecule can bind all TLC to the same site, but only one at atime.
Because each MHC molecule can bind many different peptides, binding istermed degenerate.
MHC polymorphism is determined only in the germline. There are norecombinational mechanisms for generating diversity.
MHC molecules are membrane-bound; recognition by T cells requires cell-
cell contact. Alleles for MHC genes are co-dominant. Each MHC gene product isexpressed on the cell surface of an individual nucleated cell.
A peptide must associate with a given MHC of that individual, otherwise noimmune response can occur. That is one level of control.
Mature T cells must have a T cell receptor that recognizes the peptideassociated with MHC. This is the second level of control.
Cytokines (especially interferon-) increase level of expression of MHC. Peptides from the cytosol associate with class I MHC and are recognized by
Tc cells. Peptides from within vesicles associate with class II MHC and arerecognized by Th cells.
Polymorphism in MHC is important for survival of the species.
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the 3.6-Mb MHC region on chromosome 6 contains 140genes
ame Function Expression
MHC class I
Encodes non-identical pairs(heterodimer) of peptide-binding proteins, as well
as antigen-processingmolecules such as TAP andTapasin.
All nucleated cells. MHC class I proteinscontain an chain &2-micro-globulin(not part of the MHC encoded bychromosome 15). They present antigen
fragments to cytotoxic T-cells viathe CD8 receptor on the cytotoxic T-cells and also bind inhibitory receptorson NK cells.
MHC class II
Encodes (1) heterodimeric
peptide-binding proteins and(2) proteins that modulateantigen loading onto theMHC class II peptide-binding proteins inthe lysosomal compartmentsuch as MHC II DM, MHC II
On most immune system cells, specificallyon antigen-presenting cells. MHCclass II proteins contain & chainsand they present antigen fragments toT-helper cells by binding to
the CD4 receptor on the T-helpercells.
In human HLA; in rat H2 complex
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In human HLA; in rat H2 complex
MHC III- components of the complement system (such as C2, C4 and B
factor) and molecules related with inflammation (cytokines such as TNF-,
LTA, LTB) or
heat shock proteins (hsp)
Class I MHC molecules bind peptides derived from
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Class I MHC molecules bind peptides derived fromendogenous antigens that have been processed within thecytoplasm of the cell (e.g., normal cellular proteins, tumor
proteins, or viral and bacterial proteins produced withininfected cells).
Class II MHC molecules bind peptides derived fromexogenous antigens that are internalized by phagocytosisor endocytosis and processed within the endocyticpathway.
Characteristics of the antigen processing pathways
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Characteristic MHC-I pathway MHC-II pathway
Composition of the stable peptide-
MHC complex
Polymorphic chain and 2
microglobulin, peptide bound to
chain
Polymorphic chains and ,
peptide binds to both
Types of antigen presenting
cells (APC)All nucleated cells, platelets
Dendritic cells, mononuclear
phagocytes, B lymphocytes, some
endothelial cells, epithelium
of thymus
T lymphocytes able to respond Cytotoxic T lymphocytes (CD8+) Helper T lymphocytes (CD4+)
Origin of antigenic proteins
cytosolic proteins (mostly
synthetized by the cell; may also
enter from the extracellular
medium via phagosomes)
Proteins present in endosomes
or lysosomes (mostly internalized
from extracellular medium)
Enzymes responsible for peptidegeneration Cytosolic proteasome Proteases from endosomes andlysosomes (for instance, cathepsin)
Location of loading the peptide on
the MHC moleculeEndoplasmic reticulum Specialized vesicular compartment
Molecules implicated in
transporting the peptides and
loading them on the MHCmolecules
TAP (transporter associated with
antigen processing) DM, invariant chain
Characteristics of the antigen processing pathways
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Transporter associated with antigen processing (TAP)
member of the ATP-binding-cassette transporter family
formed of two proteins: TAP-1 and TAP-2, which have onehydrophobic region and one ATP-binding region each
found in the ER lumen associated with thepeptide-loadingcomplex (PLC) consist of 2 microglobulin, calreticulin,
ERp57, TAP, tapasin, and MHC class I
Both nucleotide-binding domains (NBDs) are required forpeptide translocation, as each NBD cannot hydrolyse ATP
alone. ATP binding to TAP-1 is the initial step in the transport
process, and that ATP bound to TAP-1 induces ATP bindingin TAP-2.
Both TAP1 and TAP2 belong to the family of ATP-binding
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Both TAP1 and TAP2 belong to the family of ATP bindingcassette proteins found in the membranes of many cells,including bacteria; these proteins mediate ATP-dependent
transport of amino acids, sugars, ions, and peptides. Peptides generated in the cytosol by the proteasome are
translocated by TAP into the RER by a process that requiresthe hydrolysis of ATP
TAP has the highest affinity for peptides containing 810amino acids, which is the optimal peptide length for class IMHC binding.
TAP appears to favor peptides with hydrophobic or basiccarboxyl-terminal amino acids, the preferred anchorresidues for class I MHC molecules.
TAP is optimized to transport peptides that will interact
with class I MHC molecules.
The TAP1 and TAP2 genes map within the class II MHC
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The TAP1 and TAP2 genes map within the class II MHCregion, adjacent to the LMP2 and LMP7 genes
Both the transporter genes and these LMP genes arepolymorphic; that is, different allelic forms of these genesexist within the population
TAP deficiencies can lead to a disease syndrome that hasaspects of both immunodeficiency and autoimmunity
Within the RER membrane, a newly synthesized class Ichain associates with calnexin until 2-microglobulin bindsto the chain.
The class I chain/2-microglobulin heterodimer then binds
to calreticulin and the TAP-associated protein tapasin. When a peptide delivered by TAP is bound to the class I
molecule, folding of MHC class I is complete and it isreleased from the RER and transported through the Golgi
to the surface of the cell.
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The endocytic pathway appears to involve three
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The endocytic pathway appears to involve threeincreasingly acidic compartments: early endosomes (pH6.06.5); late endosomes, or endolysosomes (pH 5.06.0);
and lysosomes (pH 4.5
5.0). Lysosomes, for example, contain a unique collection of
more than 40 acid-dependent hydrolases, includingproteases, nucleases, glycosidases, lipases, phospholipases,
and phosphatases.
Longer peptides bulge in the middle, whereas shorter
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Longer peptides bulge in the middle, whereas shorterpeptides are more extended. Contact with the MHCmolecule is by hydrogen bonds to anchor residues 1/2 and
8/9.
human cytomegalovirus (CMV), hepatitis B virus (HBV),and adenovirus 12 (Ad12) decreases the expression ofMHC 1.
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MHCII These molecules consist of two, linked, glycoproteins (
and ), composed of 229 and 237 amino acids,
respectively Each is coded for by genes of the MHC and consists of four
regions;
two extracellular, hydrophilic regions (1 and 2, or 1and 2 domains),
a transmembraneous, hydrophobic region; and
an intracellular, hydrophilic, region that anchors the
molecule in the cell membrane. 1 and 1 domains combine to form a single peptide-
binding site composed of two a helical loops supported bya platform of eight anti-parallel b strands
Recent experiments indicate that most class II MHCinvariant chain
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pcomplexes are transported from the RER, where they are formed,through the Golgi complex and trans-Golgi network, and thenthrough the endocytic pathway, moving from early endosomes to
late endosomes, and finally to lysosomes. A short fragment of the invariant chain termed CLIP (fclass II
associated invariant chain peptide) remains bound to the class IImolecule after the invariant chain has been cleaved within the
endosomal compartment. CLIP physically occupies the peptide-binding groove of the class II
MHC molecule, presumably preventing any premature binding ofantigenic peptide
HLA-DM, a nonclassical MHC class II molecule expressed withinendosomal compartments, mediates exchange of antigenic peptidesfor CLIP.
The nonclassical class II molecule HLA-DO may act as a negative
regulator of class II antigen processing by binding to HLA-DM andinhibitin its role in the dissociation of CLIP from class II molecules.
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HLA-DM is widely conserved among mammalian species.Like other class II MHC molecules, HLA-DM is a
heterodimer of and chains. Unlike other class II molecules, HLA-DM is not
polymorphic and is not expressed at the cell membranebut is found predominantly within the endosomal
compartment.
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HLA-DO differs from HLA-DM in that it is expressed only
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p yby B cells and the thymus, and unlike other class IImolecules, its expression is not induced by IFN-.
The antigen-binding groove is open at both ends and doesnot enclose the C- and N-termini of the peptide. Thebound peptide extends beyond the antigen-binding grooveat both ends.
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Role of MHC molecules in transplant rejection
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Role of MHC molecules in transplant rejection
Each human cell expresses six MHC class-I alleles (oneHLA-A, -B, and -C allele from each progenitor) and 6-8MHC class-2 alleles (one HLA-DP and -DQ, and one ortwo HLA-DR from each progenitor, and somecombinations of these).
The MHC polymorphism is very high: It is estimated that inthe population there are at least 350 alleles for HLA-A
genes, 620 alleles for HLA-B, 400 alleles for DR, and 90alleles for DQ
All MHC molecules can be targets for transplant rejection,but HLA-C and HLA-DP molecules show lowpolymorphism, and most likely they are less important inrejection.
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B cell maturation, activation anddifferentiation
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Activation Activation of CD4+ T cells occurs through the engagement of
both the T cell receptor and CD28 on the T cell by the majorhistocompatibility complex (MHC) peptide and B7 familymembers on the APC, respectively.
Absense of co-stimullator CD28 - Anergy
I l b li
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Immunoglobulin The immunoglobulin molecule consists of three major
functional regions called the The F(ab)2 region (Fragment antigen binding) contains the
binding sites for foreign particles (or antigens),
the hinge region is where the other two meet and confers
flexibility on the molecule and Fc region (Fragment crystallisable) confers the biological
properties of the molecule
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The classic signs and symptoms of acute inflammation
English Latin
Celsus
Redness Rumor
Swelling Tumor
Heat Calor
Pain Dolor
Loss of function Functio laesa Galen
Comparison between acute and chronic
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Comparison between acute and chronic
inflammationAcute Chronic
Causative agentPathogens, injured
tissues
Persistent acute inflammation dueto non-degradable pathogens,
persistent foreign bodies, or
autoimmune reactions
Major cells involved
Neutrophils,
mononuclear cells(monocytes,
macrophages)
Mononuclear cells (monocytes,
macrophages, lymphocytes, plasma
cells), fibroblasts
Primary mediatorsVasoactive amines,
eicosanoids
IFN- and other cytokines, growth
factors, reactive oxygen species,
hydrolytic enzymesOnset Immediate Delayed
Duration Few days Up to many months, or years
Outcomes
Resolution, abscess
formation, chronic
inflammation
Tissue destruction, fibrosis, necrosis
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Plasma cascade systems
The complement system, when activated, results in the increased
removal of pathogens via opsonisation and phagocytosis.
The kinin system generates proteins capable of sustaining
vasodilatation and other physical inflammatory effects.
The coagulation system or clotting cascade which forms a protectiveprotein mesh over sites of injury.
The fibrinolysis system, which acts in opposition to the coagulation
system, to counterbalance clotting and generate several other
inflammatory mediators.
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Plasma derived mediators
Name Produced by Description
Bradykinin Kinin system A vasoactive protein which is able to induce vasodilation, increase vascularpermeability, cause smooth muscle contraction, and induce pain.
C3 Complement system Cleaves to produce C3a and C3b. C3a stimulates histamine release by mast cells,thereby producing vasodilation. C3b is able to bind to bacterial cell walls and act as an
opsonin, which marks the invader as a target for phagocytosis.
C5a Complement systemStimulates histamine release by mast cells, thereby producing vasodilation. It is also
able to act as a chemoattractant to direct cells via chemotaxis to the site of
inflammation.
Factor XII Liver A protein which circulates inactively, until activated by collagen, platelets, or exposedbasement membranes via conformational change. When activated, it in turn is able to
activate three plasma systems involved in inflammation: the kinin system, fibrinolysis
system, and coagulation system.
Membraneattack complex
Complement systemA complex of the complement proteins C5b, C6, C7, C8, and multiple units of C9. The
combination and activation of this range of complement proteins forms the membrane
attack complex, which is able to insert into bacterial cell walls and causes cell lysis with
ensuing death.
Plasmin Fibrinolysis system Able to break down fibrin clots, cleave complement protein C3, and activate Factor XII.
Thrombin Coagulation system Cleaves the soluble plasma protein fibrinogen to produce insoluble fibrin, whichaggregates to form a blood clot. Thrombin can also bind to cells via the PAR1 receptor
to trigger several other inflammatory responses, such as production of chemokines and
nitric oxide.
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