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Basic Sciences Immunology Immune Deficiencies
3 questions
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A WBC differential will reveal extremely elevated levels of neutrophils (6-10x
normal) because the integrin defects leave them unable to leave the blood vessels
Doctors often suspect LAD when the umbilical cord fails to separate within the
first few weeks of birth.
Defective integrin proteins (eg, LFA-1, Mac-1) on phagocytes
1) Defective phagocytosis
2) Defect in binding to endothelial cells defective transmigration out of the
bloodstream to sites of infection and/or inflammation
Peritonitis
Bruton's Agammaglobulinemia
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2 questions
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All lymphoid organs that normally contain mature B cells (lymph nodes,
tonsils, adenoids, Peyers patches, spleen) may be smaller. Germinal centers are
histologically absent in these organs.
4 questions
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Failure of development of the 3rd and 4th pharyngeal pouches hypoplasia of the
thymus and parathyroid glands congenital T cell deficiency
CATCH-22:
Cardiac defects: tetralogy of Fallot, VSD, many others
Abnormal facial features
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2 questions
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3 questions
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Caused by defective CD40 ligand (CD154): CD4+ T helper cells, which normally
express CD40L, are unable to induce B cells to undergo immunoglobulin class
switch (from IgM to other classes)
Presents in infancy with recurrent upper and lower respiratory infections, often with
opportunistic organisms (e.g. Pneumocystis jiroveci)
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Other, much rarer, forms of Hyper IgM syndrome exist that affect both
genders and are autosomal recessive.
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3 questions
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3 questions
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Can also occur in patients lacking T cell immunity (e.g. DiGeorge syndrome)
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3 questions
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Isolated IgA deficiency is the most common inherited B cell defect, occurs in 1 in 700
persons
Represents a failure of terminal differentiation of IgA-producing B cells: they never
mature to plasma cells IgA levels are nearly undetectable
2 questions
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Result: plasma cells with resultant hypogammaglobulinemia, most often of IgA and
IgG
Normal number of circulating B cells
Can develop during 20s-30s, presenting with recurrent bacterial infections
(sinopulmonary and GI infections), risk of autoimmune disease and lymphoma
18 questions
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6 questions
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Mutation: -chain of cytokine receptors defective signaling of IL-2, IL-4, IL7, IL-15, and others
IL-7 is necessary for lymphoid progenitor (esp. T cell) survival and
proliferation
Absent helper T cells diminished antibody production
5 questions
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Ataxia-Telangiectasia
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Basic Sciences Immunology Immune Deficiencies
2 questions
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Ataxia-Telangiectasia is an autosomal recessive disease caused by
defective ATM protein. The ATM gene (chromosome 11) is normally involved in
repair of double-strand DNA breaks defective ATM defective repair of doublestrand DNA breaks
2. Defective antibody class switching (ie, the switch from IgM to other
antibody classes is defectivegene splicing and rearrangement are required to
switch antibody class this process becomes defective when doublestrand DNA breaks cannot be remedied) levels of IgG, IgA, IgE patients
have a median lifespan of 20 years due to severe, recurrent sinopulmonary
infections
In addition to radiation sensitivity and recurrent sinopulmonary infections, AtaxiaTelangiectasia is also characterized by:
1.
Grafts
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Basic Sciences Immunology Immune Deficiencies
4 questions
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Grafts: tissue transferred from one location to another to provide structure and/or
function
Allo- and xenografts require immune suppression
1) Autograft: self grafts.
Chediak-Higashi Syndrome
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peripheral Neuropathy.
Pathophysiology is due to 2 defects:
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Defect in the synthesis, maintenance and storage of secretory granules (e.g.,
lysosomes in leukocytes, azurophilic granules in neutrophils, dense bodies in
platelets, melanin granules in melanocytes) defective granules which tend to
fuse and form giant (mega) granules. Platelets and neutrophils with giant granules
visible on peripheral blood smear are highly suggestive of Chediak-Higashi given the
appropriate clinical context.
Wiskott-Aldrich Syndrome
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Basic Sciences Immunology Immune Deficiencies
3 questions
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WAS (Wiskott-Aldrich syndrome): Humoral immunodeficiency caused by an Xlinked recessive defect in the WASP gene (chromosome Xp11) and characterized by
activation of B cells and poor antibody response to polysaccharide antigens.
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WASP is involved in:
- Actin polymerization
- Anchoring membrane bound receptors (eg, antigen receptors) to the actin
cytoskeleton.
This defect in the WASP gene results in an inability to mount an IgM response
to polysaccharide antigens IgM levels.
In classic WAS:
- IgM levels
HLA-Subtypes
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Basic Sciences Immunology Immune Deficiencies
6 questions
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6 questions
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Following the first exposure to an antigen, it takes 7-14 days for IgM
antibodies to be produced in serum sickness (production of IgG follows IgM).
If a previously immunized patient is later re-exposed to the same antigen, memory B
cells formed by the previous antigenic exposure can produce an IgG response within
12-36 hours, producing a much more acute and severe serum sickness reaction.
3) Polyarteritis nodosa: continuous inflammation of arterial walls (medium and small
arteries only) secondary to the deposition of circulating immune complexes
thrombosis and obliteration of the arterial lumen (no blood flow) distal gangrene /
focal necrosis of end organs (e.g. kidneys, but doesnt affect lungs)
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Passive Immunity
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The transfer of active humoral immunity (e.g. antibodies) from one individual
to another (e.g. IVIG infusions)
Not produced by the patients body, immunity persists only as long as the
antibodies are in the body. The half life for IgG is about 3.5 weeks (26 days).
The acquired host immune response that arises after exposure to a foreignless
agent such as an infection or a vaccination, usually involves both cell-mediated and
humoral immunity.
Memory B and T cells develop after initial exposure to foreign antigens
reinfection rapidly activates these memory cells
Usually lasts for the lifetime of the patient, but vaccine-induced immunity can
wane over time
Antigen Diversity/Variation
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Process by which an infectious organism changes its surface proteins in order
to evade a host immune response
Occurs through gene mutation, recombination, and switching. It leads to more
resilient organisms
Bacteria can alter some molecular structures (e.g. Salmonella acquiring
antigenically distinct flagellar proteins)
Complement
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Basic Sciences Immunology Immune Response
6 questions
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A system requiring nine major factors (C1-C9) which plays a role in cell lysis,
humoral immunity, and inflammation
C3b and IgG are the two primary opsonins in bacterial defense
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C1, C2, C3, C4 are key for viral neutralization
C3a, C4a, and C5a promote anaphylactic activity, such as degranulation of
mast cells
C5a is a potent chemoattractant: recruits neutrophils and other inflammatory
cells
C5b, C6, C7, C8, and C9 form the membrane attack complex (MAC) which
results in cell lysis. (Note: deficiency in these factors leads to Neisseria bacteremia)
Classic Pathway: the binding of proenzyme C1 to an Ag-Ab complex triggers a
sequential reaction resulting in cell lysis
The immunoglobulins IgG and IgM can activate the classic pathway of the less
complement system
1.
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2.
3.
Cytokines
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Basic Sciences Immunology Immune Response
11 questions
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Stimulates the proliferation and differentiation of bone marrow stem cells. Also
stimulates growth of mast cells and promotes histamine release
IL-4: secreted by CD4+ Th2 cells, macrophages, and mast cells
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IL-4 plays a role in the allergic response by promoting B cell proliferation and
IgG/IgE synthesis; also inhibits Th1 while promoting Th2 proliferation
IL-5: secreted by Th2 cells, mast cells, and eosinophils
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Promotes differentiation of B cells and IgA production. Also promotes
eosinophil production.
IL-6: secreted by Th2 cells, macrophages, B cells
Stimulates differentiation of B cells into plasma cells, promotes antibody less
secretion, and induces the production of acute phase reactants (e.g., CRP) by the
liver. IL-6 is also a potent pyrogen.
IL-8: secreted by macrophages, lymphocytes, endothelial cells
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Functions in neutrophil chemotaxis
IL-10: secreted by monocytes and to a lesser extent Th2 cells, mast cells,
macrophages
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Inhibits cytokine production by Th1 cells
Activates NK cells and promotes differentiation of naive T cells into Th1 cells
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IFN-: secreted by Th1 cells, cytotoxic T cells, dendritic cells, and NK cells
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Type II Hypersensitivity
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Basic Sciences Immunology Immune Response
3 questions
enter the mothers circulation during placental delivery this prevents stimulation of
the maternal immune system and injury to future Rh newborns
Type I Hypersensitivity
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Basic Sciences Immunology Immune Response
4 questions
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Late Phase: Leukotrienes are synthesized via the lipoxygenase pathway and
are released up to 6 hours after exposure. These mediators are also called slow
reacting substances of anaphylaxis (SRS-A).
Major Mediators of Type I Hypersensitivity
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Thus, eosinophils are now believed to amplify and sustain the inflammatory
response, thus necessitating treatment with corticosteroids.
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The major mediators of anaphylaxis are IgE, TNF-, IL-4, IL-6, platelet
activating factor (PAF), leukotrienes, prostaglandins, and histamine
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Interferons
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Basic Sciences Immunology Immune Response
4 questions
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Interferons are cytokines that are produced in response to the presence of viruses,
parasites, and tumor cells
They have antiviral properties: IFN- is one treatment for chronic hepatitis C
infection
IFNs activate macrophages, thereby the presentation of antigens to T cells.
IFNs also activate and enhance the functionality of NK cells.
Interferons can pass through the blood-brain barrier
IFN- delayed-type hypersensitivity; this involves activation of macrophages and
the release of TNF-
6 questions
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Helper T cells express CD3, CD4, CD28, CD40L, and TCR (T-cell receptor)
Cytotoxic T cells express CD3, CD8, CD28, and TCR
B cells express B7, CD19, CD20, CD21, CD40, IgM, Fc receptors, and MHC-II
Macrophages express B7, CD14, CD40, MHC-II, and receptors for Fc and C3b (a
complement component)
NK cells express receptors for MHC-I, CD16, and CD56
All nucleated cells express MHC-I (exception would be anucleate cells, such as
mature RBCs)
Type IV Hypersensitivity
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Basic Sciences Immunology Immune Response
4 questions
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Rheumatoid factor (IgM) can react with the Fc domain of IgG molecules less
IgM-IgG complexes that deposit in synovial tissue. This causes initiation of the
complement cascade and release of cytokines which activate cell mediated immunity
and T-cell mediated damage to bone, cartilage and the synovium.
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Innate immunity: includes many cellular and humoral devices, from nonspecific
barriers (e.g., skin) to recognition and destruction of specific pathogens (e.g.,
complement-mediated opsonization of microorganisms for subsequent
phagocytosis).
Spleen
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Basic Sciences Immunology Lymphoid Organs and Lymphocytes
9 questions
During development, the spleen is responsible for fetal erythropoiesis between the
second to seventh months (the liver and bone marrow are also partially responsible
for hematopoiesis during this time as well). Splenic erythropoiesis after birth is
usually pathogenic.
Grossly, the spleen is composed of a capsule and two distinct areas termed red
pulp andwhite pulp, separated by the marginal zone (capsule red pulp
marginal zone white pulp, from outside in).
Blood is filtered through the spleen via the following route: splenic artery
trabecular arteries central arteries (surrounded by white pulp) sinusoids (in
red pulp) red pulp veins trabecular veins splenic vein (notice how blood
flows from inside the spleen towards the capsule, i.e. white pulp to red pulp)
The white pulp is a major center for production and development of lymphocytes.
Within the white pulp, exists the periarteriolar lymphatic sheath
(PALS) and lymphoid nodulescalled Malpighian corpuscles (not to be confused
with Malpighian renal corpuscles).
The periarterial lymphatic sheath (PALS) surrounds the central arteriole in less
the
white pulp and is composed of T cells. Dendritic cells may also be found in
the PALS area, functioning as APCs for their neighboring T cells.
Sinusoids are marked by gaps in the endothelium that assist in the filtration
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of blood. Abnormal and/or aged red blood cells become trapped as they attempt to
squeeze through the narrow spaces of the sinusoids. The trapped cells are
subsequently removed by splenic macrophages.
Macrophages lining the splenic cords of billroth in the red pulp sample
sinusoidal blood by extending processes through gaps in the sinusoidal endothelium
and basement membrane. Here, they function to remove old and damaged red blood
cells as well as encapsulated bacteria (recall SHiNE SKiS mnemonic for
encapsulated bacteria S. pneumonia, H. influenza type B, N. meningitides, E. coli,
Salmonella, K. pneumonia, Group B Strep).
Target cells
Thrombocytosis
SAD PUCKER
Mnemonic
Immunoglobulins
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1 question
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IgG and IgM are capable of activating the classical pathway of the
complement cascade. Due to the pentameric structure of its secreted form, IgM is
more efficient at activating the classical complement pathway than IgG.
IgA is capable of activating the:
- alternative pathway of the complement cascade
- mannan-binding lectin pathway of the complement cascade
Has four subclasses (IgG1, IgG2, IgG3, IgG4) which are differentiated by slight
variations of the heavy chain, and perform slightly different functions.
Capable of executing all the functions of the immunoglobulins
Protects the body via four mechanisms of action:
1. Agglutination and immobilization
2. Fixing/activating complement
3. Opsonization for phagocytosis
4. Neutralizing bacterial toxins
IgA:
Second most common Ig (immunoglobulin) in serum
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Most common Ig overall this makes sense given the tremendous mucosal surface
area of the human body and the fact that IgA is the primary Ig secreted to protect
mucosal surfaces
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IgM = first Ig made by a B cell following the first exposure of that B cell to its
cognate antigen.
Pentameric structure (5 IgMs held together by a J-chain 10 total antigen
binding sites!) of the secreted form of IgM makes it the most efficient at:
- agglutinating Ig
- activating the classical pathway of the complement cascade
Exists as a monomer when attached to B cell surfaces while functioning as an
antigen receptor
The spleen is a site for IgM synthesis.
IgD is located on the surface of nave B cells and trace amounts of IgD may
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be detected in serum, however the functional significance of IgD in either of these
locations remains unclear.
IgD cannot fix complement.
IgE:
Serum levels of IgE tend to rise during infections with invasive helminths (e.g.,
Strongyloides, Trichinella, Ascaris, Necator, Ancylostoma).
Immunoglobulin isotype, allotype, and idiotype:
- unlike isotypes, which are species-wide, allotypes can vary among members of a
given species
Idiotype:
- defined by the amino acid sequence and corresponding 3-dimensional structure of
thevariable region of the immunoglobulin molecule
- reflects similarities in the variable region for a given antigen among a group of Ig or
T cell receptors
- idiotypes are highly variable from person to person
B cells
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8 questions
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Although B-cells and T-cells both originate in the bone marrow from lymphoid stem
cells, T-cells mature in the thymus whereas B-cells mature in the bone marrow:
Lymphoid stem cell pro-B cell (progenitor) pre-B cell (cytoplasmic )
immature B cell (surface IgM), which is released into the circulation and is called a
mature (nave) B cell when it simultaneously expresses both surface IgM+ and IgD+
(via alternative splicing).
B cell markers: CD 19, CD 20, CD 21
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Each B cells antigen specificity (idiotype) is determined by the threedimensional shape formed by the N-terminal of heavy and light chains (at the tips of
the Y).
B cells that are reactive to self antigens undergo clonal deletion in the bone
marrow or are inactivated in the periphery (clonal anergy).
During B-cell maturation, 4 things contribute to idiotypic diversity:
2) Gene recombination:
VDJ recombination diversity of heavy chain variable domains
VJ recombination diversity of light chain variable domains
3) N-nucleotide addition: Tdt (terminal deoxynucleotidyl transferase) randomly
inserts nucleotides into the DNA sequence at the junctions of V, D, and J segments.
- In B cells, Tdt is only active during recombination of heavy chain gene segments
(VDJrecombination), not active during recombination of light chain gene segments
(VJ recombination).
- In T cells, Tdt is active during rearrangement of all gene segments in the formation
ofTCR (T-cell receptor).
4) Combinatorial diversity: Refers to 2 processes during B cell maturation:
-Variable arrangement of receptor gene segments
-Any heavy chain can associate with any light chain different heavy chain-light
chain combinations form different epitopes
Type 1: An antigen called a mitogen (e.g., the highly repetitive surface less
structure of certain parasites) can bind B cell surface molecules that are not B cell
receptors but are nevertheless linked to B cell receptors clustering of mitogen-
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Definition:
Mature nave lymphocytes = immunocompetent B- and T-cells which have already
completed the selection process in the bone marrow and thymus, respectively, but
have not yet been stimulated by foreign antigen.
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T cells
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Basic Sciences Immunology Lymphoid Organs and Lymphocytes
1 question
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CD2 and CD3, which are important in signal transduction, are major markers
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of all peripheral T cells
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T cells recognize only polypeptide antigens. These antigens must be
presented in conjunction with MHC proteins.
CD4 Th1 cells produce IFN-, macrophage activation.
CD4 Th2 cells help activate B cells to make antibodies.
CD8+ T cells directly kill virus-infected cells, tumor cells, and donor graft cells.
T cells are involved in delayed cell-mediated hypersensitivity (type IV)
T cells mediate allograft rejection, both acute and chronic. [Note: B cells are
also involved in organ transplant rejection]
Helper (CD4+) T cell activation:
In the absence of the second signal, a state of anergy occurs where the cell
becomes unresponsive to that particular epitope.
Cytotoxic (CD8+) T cell activation:
First signal: Antigen presentation via MHC-I of a virus-infected cell. This less
is
recognized by TCR on the cytotoxic T cell. The CD8 co-receptor stabilizes this
interaction.
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Positive selection induces apoptosis of cells that bind too weakly while
negative selection induces apoptosis of cells that bind too strongly. Cells with highmedium binding survive. Binding refers to the ability of the T-cell receptors to bind to
either MHC class I/II or peptide molecules.
All T cells originate from hematopoietic stem cells in the bone marrow,
howeverdevelopment takes place in the thymus.
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Note: only 1-2 percent of T cells leave the thymus; most of the remaining T
cells undergoapoptosis.
T-cells are described based on their cell surface proteins: either CD4 or CD8
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CD4+ T cells develop into helper T cells in the thymusTh1 cells and Th2
cells:
- Th1 cells coordinate a CMI (cell-mediated immune) response and inhibit a Th2stimulated humoral response.
- Th2 cells coordinate a humoral immune response and suppress a Th1stimulated CMIresponse.
CD4+ cells are further divided into Th1 and Th2 cells
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Th1 cells coordinate a cell-mediated immune response to
eradicate intracellular pathogens (eg, Listeria, mycobacteria, Leishmania):
1. Intracellular pathogens stimulate a strong innate immune response. Macrophages
and NK cells induce differentiation of pleuripotent Th0 cells into Th1 cells is
driven via IL-12 production by macrophages and IFN- production by NK cells.
2. Th1 cells secrete IL-2, IFN-, TNF-, and TNF-
3. IFN- produced by Th1 cells promotes further development of Th1 cells.
4. Proliferation of Th1 cells is inhibited by IL-4 and IL-10 produced by Th2 cells.
cells into Th2 cells is the default pathway and is driven by constitutive elaboration of
IL-4 by the naive Th0 cells themselves
2. Th2 cells secrete IL-4, IL-5, IL-6, IL-10, IL-13, and TGF
3. IL-4 and IL-10 produced by Th2 cells promote further development of Th2 cells.
4. Proliferation of Th2 cells is inhibited by IFN- produced by Th1 cells.
Lymph Node
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5 questions
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Lymph nodes are secondary lymphoid organs that perform 2 main functions:
Paracortex = site where antigen is presented (by APCs) to T helper cells and
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some B cells stimulated B and T cells travel to the cortex to activate the primary
follicles, forming secondary follicles with germinal centers
Paracortical size / cellularity varies depending on underlying pathology for
example:
1. In immunocompetent patients, certain types of infections stimulate
lymphocyte proliferation number of circulating lymphocytes
hyperplastic, larger-than-normalparacortex due to massive lymphocyte influx
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Medullary cords are rich with antibody-producing plasma cells
These antibodies exit the lymph node via cortical sinuses, which drain into the
medullary sinuses, then into the efferent lymphatics
Deep lymphatics of the arm and the pectoral region axillary nodes
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Stomach peri-gastric and gastro-omental nodes celiac lymph nodes
Duodenum pancreaticoduodenal and pyloric lymph nodes.
Jejunum, ileum, ascending (right) colon, and transverse colon superior
mesenteric nodes
Descending (left) and sigmoid colon inferior mesenteric lymph nodes. The
splenic flexure can drain to both the superior and inferior mesenteric nodes
Inferior rectum and anal canal proximal to the pectinate line internal iliac
nodes
Anal canal below the pectinate line superficial inguinal nodes
Posterior abdominal wall, kidneys, testes or ovaries, and uterus para-aortic
and para-caval nodes
Testes para-aortic nodes
Scrotum superficial inguinal nodes
It starts by draining the main abdominal lymphatic ducts, all of which empty into the
thoracic duct by the level of T12.
The thoracic duct passes through the diaphragm into the posterior mediastinum,
where it continues to collect drainage mainly from the left upper quadrant of the
body.
Then it empties into the venous system at the left venous angle (juncture of the left
subclavian and internal jugular veins)
Antibody Structure
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3 questions
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Antibody Structure
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A "Y" shaped molecule made of 2 heavy chains and 2 light chains, which are
termed based on their molecular weights.
The 4 chains are linked by disulfide bonds
The tips of the "Y" are the variable regions that recognize antigens
The tips involve both heavy and light chains
Heavy Chain
Most H chains consist of 1 variable and 1 constant domain.
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Light Chain
L chains are either (kappa) or (lambda). Either one can be found in anyless
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the 5 different Ig classes, however each particular Ig molecule only contains either
or .
Light chain is not found in the Fc portion. The N-terminus of the L chain is
involved in the antigen binding site.
Papain is a proteolytic enzyme often used in experiments. It cleaves the peptide
bonds at thehinge region of the antibody 2 identical Fab fragments (which can
bind antigen) and 1 Fc fragment (which can bind complement).
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Expressed on virtually all cells and usually present antigens that
are synthesized withinthe actual cell.
Encoded by the following Human Leukocyte Antigen (HLA) genes: HLAA, HLA-B, HLA-C
Antigens created from intracellular (cytoplasmic) peptides are loaded in the
rough endoplasmic reticulum. External Flash animation
MHC-I-dependent antigen presentation is the primary way for a virus-infected
cell to activate T cells
A virally infected cell will present viral glycoproteins on its surface in
conjunction withclass I MHC proteins:
-This causes CD8 T cells to bind via antigen-specific receptor to the MHC protein
complex.
-Th cells secrete IL-2 activation of CD8 cell death of only virally infected cell.
Phagocytosed antigens are digested and loaded onto MHC-II from acidified
endosomes.External Flash animation
Major Histocompatibility Complex-III (MHC-III)
The function of the MHC-III region differs from MHC-I & MHC-II: the MHC-less
III region encodes for complement (e.g. C2, C4) and tumor necrosis factors
(e.g. TNF-)