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Leukocyte Adhesion Deficiency Syndrome

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Basic Sciences Immunology Immune Deficiencies

3 questions
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A rare primary immunodeficiency characterized by defective phagocytic cells and


marked leukocytosis due to defective/absent integrin proteins on phagocytic
cells

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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

Most patients express no CD18, an essential 2-integrin on lymphocytes, less


macrophages, and neutrophils which is required for:
1) Lymphocyte interactions with antigen presenting cells (e.g., neutrophils, dendritic
cells)
2) Leukocyte adhesion to endothelial cells, which is a necessary first step for
leukocyte migration to sites of infection and inflammation
3) Phagocytosis of bacteria opsonized with complement component C3b (specifically
iC3b, a proteolytically inactive form of C3b capable of opsonization).
Leukocyte adhesion deficiency presents in the neonatal period with recurrent
bacterial infections. Notably, there is an absence of pus formation associated with
these infections (due to impaired neutrophil migration)
Some of the presenting infections may include:

Notably, there is an absence of pus formation associated with these infections


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(due to impaired neutrophil migration)
Omphalitis
Pneumonia
Gingivitis

Peritonitis

Bruton's Agammaglobulinemia

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Basic Sciences Immunology Immune Deficiencies

2 questions
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Bruton Agammaglobulinemia: X-linked recessive disorder caused by a mutation in


the BTK(Bruton tyrosine kinase) gene absent or defective BTK.

Normally, BTK is required to mature a developing B lymphocyte past the preless


B cell stage
absent or defective BTK arrested development of pre-B cells absent or
levels of mature B cells plasma cell deficiency absence or levels of all
classes of immunoglobulins susceptibility to bacterial infections

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.

X-linked recessive Bruton agammaglobulinemia usually affects males only;


heterozygous female carriers of the BTK mutation usually have no symptoms.
Bruton agammaglobulinemia is usually diagnosed in male infants when levels of
maternal IgG decline (around 4-6 months of age) affected children often
present with a long history of recurrent bacterial infections.

Cell-mediated immunity is unaffected the immune response against viralless


infections remains robust

DiGeorge's Syndrome (Thymic Hypoplasia)


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Basic Sciences Immunology Immune Deficiencies

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

Genetics: chromosome 22q11.2 deletion syndrome (ie, there is a deletion


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of
about 30-40 genes at location 11.2 on the long arm of chromosome 22)

CATCH-22:
Cardiac defects: tetralogy of Fallot, VSD, many others
Abnormal facial features

Thymic aplasia T-cell dysfunction/deficiency


Cleft palate
Hypocalcemia: due to hypoparathyroidism
22q11.2 microdeletion
Secondary cases result from teratogen (e.g. alcohol) exposure during weeks 4-6 of
fetal development
Clinical manifestations
Recurrent viral and fungal infections from T cell deficiency

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Tetany from hypoparathyroidism with hypocalcemia


Associated with congenital defects of heart and great vessels (Tetralogy of Fallot),
mandible (cleft palate), and ear aka velocardiofacial syndrome (VCFS)
Congenital heart disease is the most common cause of death. Severe immune
deficiency is the second most common cause

Interleukin 12 Receptor Deficiency


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Basic Sciences Immunology Immune Deficiencies

2 questions
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Discovered in otherwise healthy patients with disseminated mycobacterial and


salmonella infections
The IL-12 receptor deficiency decreased production of IFN- by Th1 cells and NK
cells
IFN- is still secreted in an IL-12 independent manner so granulomas form, but the
infection is inadequately controlled by the cell-mediated immunity

Hyper IgM Syndrome


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Basic Sciences Immunology Immune Deficiencies

3 questions
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Characterized by the failure of antibodies to switch classes from IgM to IgA/IgG/IgE


once an antigen is recognized

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)

Diagnosis: very low levels of IgG/IgA/IgE, patients typically have a low


number of neutrophils, IgM levels can be elevated or normal
The most common form is inherited as an X-linked trait only present in boys

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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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Job Syndrome (Hyper IgE Syndrome)


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Basic Sciences Immunology Immune Deficiencies

3 questions
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Characterized by neutrophil chemotaxis leads to recurrent staphylococcal


infections that are cold to the touch
Caused by failure of T helper cells to produce IFN- (required for macrophage
activation and migration)
Presents with FATED features:
Facies (coarse)
Abscesses (Staphylococcal, cold to the touch)
Teeth (primary teeth are retained)
Elevated concentrations of serum IgE
Dermatologic problems (eczema)

Chronic Mucocutaneous Candidiasis


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Basic Sciences Immunology Immune Deficiencies

3 questions
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Chronic C. albicans infections caused by a limited defect of helper T cell function


Pathophysiology: T cell cytokine production, specifically IL-2 and IFN-

Can also occur in patients lacking T cell immunity (e.g. DiGeorge syndrome)
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Presents in infancy with cutaneous, mucous membrane, or disseminated candidal


infections
Associated with several genetic disorders, including:
- Autoimmune polyendocrinopathy syndrome type I (APCED)
- Thyroid disease (chromosome 2p)
- Hyper-IgE syndrome

Isolated IgA Deficiency


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Basic Sciences Immunology Immune Deficiencies

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

Because the defect is specific to IgA-lineage B cells, the other


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immunoglobulins are normal
Patients with IgA deficiency commonly present with:
1. Infections, especially those involving mucosal surfaces e.g., URIs (upper
respiratory tract infections)
2. Anaphylactic reactions to transfused blood containing IgA (because their
immune system perceives IgA in the transfused blood as foreign produce antiIgA antibodies (IgG) which attack the transfused IgA) patients with IgA deficiency
should receive blood transfusions with blood that lacks IgA (e.g., blood from patients
who are also IgA deficient)
3. Diarrhea
4. Milk allergies

Common Variable Immunodeficiency


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Basic Sciences Immunology Immune Deficiencies

2 questions
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Diverse group of disorders that share a failure of terminal B-cell maturation

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

Autoantibodies and Associated Disorders


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Basic Sciences Immunology Immune Deficiencies

18 questions
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Listed below are autoantibodies and their associated disorders:


ANA (anti-nuclear antibodies = non-specific antibodies against antigens within
the nucleus): SLE (systemic lupus erythematous); Sjgrens syndrome;
Scleroderma (systemic sclerosis)
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Anti-dsDNA and anti-Smith are specific for SLE

Anti-histone: Drug-induced lupus


Anti-SS-A (anti-Ro) and anti-SS-B (anti-La) are associated with Sjogrens
syndrome
Rheumatoid factor (anti-IgG antibodies = autoantibodies (mostly IgM) directed
against the Fc portion of IgG): Rheumatoid arthritis; Sjgrens syndrome

anti-CCP (anti-cyclic citrullinated peptide antibodies = autoantibodiesless


against citrulline-modified peptides): relatively specific for rheumatoid arthritis
Anti-centromere (autoantibodies against centromeric
proteins): CREST syndrome (subset of limited scleroderma (systemic sclerosis))

Anti-Scl-70 (antibodies against DNA topoisomerase I) and anti-RNA Polless


III(antibodies against RNA polymerase III) are associated with scleroderma
(systemic sclerosis), especially diffuse scleroderma
Anti-Jo-1 (antibody against histidyl-tRNA-synthetase antigen): Polymyositis;
Dermatomyositis
Anti-U1 RNP (antibodies against a U1 ribonucleoprotein complex, especially
the 70kD epitope): Mixed connective tissue disease
Anti-mitochondrial: Primary biliary cirrhosis
Anti-smooth muscle: Autoimmune hepatitis
Anti-transglutaminase, anti-gliadin and anti-endomysial: Celiac disease

Anti-GBM (anti-glomerular basement membrane antibodies = autoantibodies


against the Goodpasture antigen a peptide within the noncollagenous
portion of the 3 chain of type IV collagen): Goodpasture syndrome
Anti-desmoglein (autoantibodies against desmoglein-1 and desmoglein-3 in
the desmosomes that form intercellular junctions between keratinocytes in the
epidermis): Pemphigus vulgaris
Anti-hemidesmosome (autoantibodies against bullous pemphigus antigens 1
and 2 in the type XVII collagen components of hemidesmosomes): Bullous
pemphigoid
Anti-microsomal (anti-TPO (thyroid peroxidase)) and anti-thyroglobulin are
associated with Hashimoto thyroiditis
Anti-TSH receptor: Graves disease
Note: anti-TSH receptor antibodies is an umbrella term including TSIs (thyroidstimulating immunoglobulin, which binds the TSH receptor and mimics the action
of TSH), TGSIs (thyroid growth-stimulating immunoglobulins), and TSH-binding
inhibitor immunoglobulins
Anti-glutamate decarboxylase: Type 1 diabetes mellitus
Anti-21-hydroxylase: Addison disease (primary chronic adrenocortical insufficiency)
Anti-proteinase 3 (PR3-ANCA, formerly known as c-ANCA (cytoplasmic
antineutrophil-cytoplasmic antibodies)): Wegener granulomatosis
Anti-myeloperoxidase (MPO-ANCA, formerly known as p-ANCA (perinuclear
antineutrophil-cytoplasmic antibodies)): Churg-Strauss syndrome and
Microscopic polyangiitis;

Severe Combined Immunodeficiency


Disease
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Basic Sciences Immunology Immune Deficiencies

6 questions
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Caused by any one of a variety of defects in early stem cell differentiation


markeddeficiency of both B and T cells both humoral and cell-mediated immune
responses are affected.
Patients present with recurrent opportunistic infections (bacterial, viral, fungal,
protozoan), chronic diarrhea, and lesions of the throat and mouth.
High incidence of malignant lymphomas

Occurs in both autosomal recessive and X-linked recessive forms


X-linked recessive form account for 50-60% of cases more common in boys

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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

IL-15 deficiency: numbers of NK cells


Autosomal recessive deficiencies may also cause SCID:

50% of autosomal recessive cases are caused by ADA (adenosine


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deaminase) deficiency:
Lack of ADA accumulation of dATP high levels of dATP inhibit ribonucleotide
reductase (enzyme responsible for generating dNTPs from rNTPs) absence of
dNTPs prevents cells from undergoing rapid DNA replication (e.g., lymphocytes in
response to antigenic stimulation).
Bare Lymphocyte Syndrome is another autosomal recessive form of SCID that
is caused by mutations in the genes required to express MHC-II.
Omenn Syndrome is an autosomal recessive form of SCID that is caused by
nonsense mutations in the genes involved in early VDJ recombination (RAG1 or
RAG2) withoutVDJ recombination these patients cannot produce functional
lymphocytes.

Less commonly, a mutation in JAK3 (chromosome 19), which is the target


of the IL-2 receptor (afflicted in the X-linked form), can result in SCID.

Chronic Granulomatous Disease


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Basic Sciences Immunology Immune Deficiencies

5 questions
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CGD (Chronic Granulomatous Disease): Deficiency in NADPH oxidase. This


defect in oxygen dependent bactericidal activity causes increased susceptibility for
recurrent bacterial infections. There are 2 commonly inheritable forms:
-X-linked recessive: (Most common) defect in membrane bound components of
phagocyte oxidase microbiocidal activity.
-Autosomal recessive: defect in cytoplasmic component of phagocyte oxidase.
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Child is susceptible to infection by catalase positive organisms but can resist


catalase negative organisms because the H2O2 made by these bacteria can be used
by MPO.
S/Sx observed in patients with CGD (chronic granulomatous disease):

1) Recurrent infections (e.g., osteomyelitis; deep soft tissue abscesses;


severe pneumonia) w/ catalase-positive organisms
- lymphadenopathy
- hypergammaglobulinemia
- white blood cell count

2) Inadequate neutrophil defense macrophages wall off microbes and


formgranulomas hepatosplenomegaly secondary to granuloma formation
Dx: negative NBT (nitroblue tetrazolium) dye reduction test; phagocyte oxidase
negative

Normal phagocytes exposed to NBT develop blue inclusions indicative of aless


normal respiratory burst. If blue inclusions dont develop, the test is negative and
suggests CGD.
Catalase-positive organisms are phagocytosed but cannot be killed because they
degrade their own H2O2
Because enzyme-deficient neutrophils cannot produce H2O2 and bacterial less
H2O2 is destroyed by bacterial catalase, H2O2 is not available as a substrate for
myeloperoxidase the myeloperoxidase-halide bacteriocidal system fails to kill
catalase-positive organisms.

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Remember catalase-positive organisms SPANS KEC:


S. aureus
Pseudomonas
Aspergillus
Nocardia
Serratia
Klebsiella
E. coli
Candida
Catalase-negative organisms are phagocytosed and killed because they produce
and excrete sufficient H2O2 to permit oxygen-dependent myeloperoxidase-halide
bactericidal activity

NADPH oxidase-deficient neutrophils cannot produce their own ROS (e.g.,less


superoxide) and thus cannot produce H2O2 either.
However, bacterial H2O2 is produced and excreted by catalase-negative organisms in

sufficient amounts NADPH oxidase-deficient phagocytes can hijack this


exogenously produced H2O2 and use it as substrate for their myeloperoxidase-halide
bactericidal system kill catalase-negative organisms!

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

1. Cells become sensitive to X-ray irradiation (because X-rays have


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sufficient energy to cause double-strand DNA breaks), but not to UV irradiation
(which causes formation of aberrant thymine-thymine dimers and other more subtle
forms of DNA damage)

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.

Development of ocular telangiectasias, usually by age 5

Compromised cerebellar development, with onset of truncal ataxia as a toddler and


later development of peripheral ataxia with chorea, athetosis, dystonia, and myoclonus

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.

Bone marrow, skin grafts, cartilage, and bone


2) Syngeneic graft: from an identical twin or clone
3) Allograft: from another individual of the same species

Examples include skin transplants, corneal transplants, heart transplants, less


liver transplants, and bone marrow transplants
4) Xenograft: grafts from a different species

Example: bovine (cow) heart valves

These types of grafts have the highest incidence of immune rejection

Chediak-Higashi Syndrome
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Basic Sciences Immunology Immune Deficiencies

1 question
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Chediak-Higashi syndrome is an autosomal recessive disorder. To remember the


symptoms, use the mnemonic BALIN:

Bleeding and bruising due to platelet dysfunction.


partial Albinism due to defective melanocytes
Leukopenia (especially neutropenia) recurrent pyogenic staph and
strep Infections.

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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.

Defect in the LYST (lysosomal trafficking) protein defect in microtubule


function in neutrophils and macrophages
1) defective chemotaxis
2) prevents fusion of lysosomes w/ phagosomes formation of
phagolysosomes bactericidal defect

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

- IgA and IgE levels


- IgG levels are normal.
Classic triadTIE:
1. Profound Thrombocytopenia (<70,000 platelets/mm2)may result in purpura,
bleeding
2. Recurrent pyogenic Infectionseg, otitis media, pneumonia
3. Chronic Eczema
In addition, defects in WASP also result in:
4. Small ineffective platelets
5. risk of autoimmune disease
12% chance of developing Non-Hodgkins Lymphoma

HLA-Subtypes
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Basic Sciences Immunology Immune Deficiencies

6 questions
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Listed below are HLA-subtypes with their associated pathological conditions


HLA-A3: Hemochromatosis
HLA-B27: mnemonic PAIR:
Psoriasis
Ankylosing spondylitis
Inflammatory bowel disease
Reiter syndrome
HLA-B8: Graves disease
HLA-DQ: Systemic Lupus Erythematosus
HLA-DQ2, HLA-DQ8: Celiac disease
HLA-DR2: Multiple sclerosis; hay fever; SLE (systemic lupus erythematous);
Goodpasture syndrome
HLA-DR3: Graves disease; Type 1 diabetes mellitus, Sjogrens disease, SLE
HLA-DR4: Rheumatoid arthritis; Type I diabetes mellitus
HLA-DR5: Pernicious anemia (which causes vitamin B12 deficiency); Hashimoto
thyroiditis
HLA-DR7: Steroid-responsive nephrotic syndrome (minimal-change disease)

Type III Hypersensitivity

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Basic Sciences Immunology Immune Response

6 questions
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Type III Hypersensitivity: immune complex reactions


Circulating antigen-antibody complexes deposit on the surface of blood vessels
activating complement that eventually leads to tissue destruction. (If the complexes
are formed extravascularly, they are called in situ immune complexes).
Examples include: SLE (systemic lupus erythematosus), PAN (polyarteritisless
nodosum),PSGN (poststreptococcal glomerulonephritis), serum sickness, Arthus
reaction, and hypersensitivity pneumonitis
1) Arthus Reaction: localized area of tissue necrosis resulting from acute immune
complex vasculitis, resulting from antigen-antibody complex that precipitate in vessel
walls (causing fibrinoid necrosis)
Occurs in highly sensitized humans injected with antigen complement isless
activated chemotactic factors (C3a, C5a) cause neutrophil infiltration and platelets
produce thrombi, ultimately yielding hemorrhagic, necrotic lesions
2) Serum sickness: formed immune complexes deposit in membranes where they fix
complement tissue damage
Caused by injection of foreign serum or drugs (e.g. sulfonamides, penicillin,
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cephalosporins, phenytoin, and thiourea)
Patients present with fever, pruritic rash, proteinuria, lymphadenopathy, and
joint pain

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)

30% of patients have hepatitis B surface antigen-antibody complexes; less


loose association with p-ANCA
4) Glomerulonephritis: antigen-antibody complexes deposit on the renal glomerular
basement membrane inflammatory response
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Most commonly implicated antigens: DNA, insulin, thyroglobulin, group A


streptococci, and foreign serum

Diagnosis: complexes detected using fluorescent antibody against the


antigen, antibody, or complement. A "lumpy-bumpy" pattern of fluorescence results
from the random deposition of the complexes.
5) SLE: formation of autoantibodies to endogenous antigens such as double
stranded RNA(dsRNA), nuclear antigens (ANA-antinuclear antibodies, anti-dsDNA),
as well as RBCs, WBCs, and platelets,

Passive & Active Immunity


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Basic Sciences Immunology Immune Response

1 question
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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).

Other examples of passive immunity: human tetanus immune globulin given


to treat tetanus, a baby receiving antibodies in his mothers breast milk
Active Immunity

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)

Antigenic drift is the process of random accumulation of mutations in viral


genes. These changes are usually minor enough that the host immune response is
still able to rapidly respond to the infection without much injury to the host.
Antigenic shift is the process by which at least two different strains of a virus
(or different viruses), combine to form a new subtype having a mixture of the surface
antigens of the two original strains (i.e. Borrelia recurrentis in relapsing fever).
Antigenic shifts may result in changes in antigen structure that evade the host
immune system, resulting in much more serious infections.
Influenza shift includes rearrangement of its viral genomic RNA segments;
shifts represent drastic changes and can cause pandemics. Drift includes more
minor changes due to mutation of hemagglutinin and/or neuraminidase, but which
the immune response is still able to respond to without major injury.
Anergy
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Lack of reaction by the bodys immune system to antigens
T-cell anergy can arise when the T-cell receives only 1 of the 2 required
stimulatory signals during antigen recognition
Clinical example: in lepromatous leprosy, the cellular response to many nontuberculoid antigens is suppressed
B-cell anergy is a key mechanism for self-tolerance in B-cells
B-cell anergy can occur with exposure to a circulating autoantigen, and is
marked by surface IgM levels and modification of intracellular signaling pathways
B-cell anergy is less complete than in T cells

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

Mannose-binding lectin pathway: mannitose-binding lectin replaces C1q; does


not need the presence of antibodies to be activated
Alternate Pathway: activated by cell wall components from certain bacteria and
yeasts, endotoxin, and aggregated IgA. Does not require antibody, C1, C4, or C2
Decay accelerating factor (DAF, also known as CD55) inhibits the assembly of C3
convertases; DAF and C1 esterase inhibitor both prevent inappropriate complement
activation

Mutations of C1 esterase inhibitor can lead to hereditary angioedema


and HUS (hemolytic uremic syndrome)

Deficiency of DAF complement-mediated lysis of RBCs paroxysmal


nocturnal hemoglobinuria (PNH)
PNH (paroxysmal nocturnal hemoglobinuria):

PNH is caused by acquired, inactivating somatic mutations in


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the PIGA(phosphatidylinositol glycan complementation group A) gene in
hematopoietic stem cells deficiency of GPI (glycosylphosphatidylinositol)linked proteins, including 3GPI-linked proteins that regulate complement (decayaccelerating factor (CD55), membrane inhibitor of reactive lysis (CD 59), C8 binding
protein) susceptibility of RBCs, WBCs, and platelets to complementmediated lysis
The hemolysis in PNH is usually chronic (as opposed to paroxysmal) and
occurs throughout the day (as opposed to nocturnal), and the hemoglobinuria
of PNH is usuallynot dramaticthe hemolysis is only paroxysmal and nocturnal in
25% of cases ( respiratory rate during sleep respiratory acidosis blood pH
complement activity, hence the increased tendency for RBCs to lyse at night in
~25% of patients withPNH)
Suspect PNH in patients with:

1.

Hemolytic anemia (intravascular hemolysis secondary to C5b-C9


membrane attack complex formation)

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2.

Hypercoagulable state due to platelet dysfunction (secondary to


deficient GPI-linked proteins on platelets) recurrent venous thrombosis is
common, often involving the portal vein, hepatic veins, or cerebral veins; thrombosis
= most common cause of death in PNH

3.

PancytopeniaPNH is often associated with aplastic anemia (ie, bone


marrow failure)

PNH is now diagnosed by demonstrating RBCs deficient in GPI-linked


proteins (eg, decay-accelerating factor (CD55), membrane inhibitor of reactive lysis
(CD 59), C8 binding protein) on flow cytometry.
Classic tests for PNH:
- Screen for PNH with sucrose hemolysis (sugar water) test
- Confirm PNH with acidified serum (Ham) test: acidified serum activates
alternative complement pathway to cause hemolysis
Lack of C3 or any other activator proteins can predispose to severe, recurrent
pyogenic sinus and respiratory tract infections
Deficiency of the terminal pathway (C5, C6, C7, and C8) predisposes to Neisseria
infections

Cytokines
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Basic Sciences Immunology Immune Response

11 questions
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IL-1: secreted by macrophages, B cells, monocytes, and osteoblasts

In addition to its role as an endogenous pyrogen (i.e., induces fever), IL-1less


performs several important functions:

- Stimulates T helper cells, induces B cells to multiply


- Stimulates acute inflammation, activates endothelial adhesion molecules
- Activates osteoclasts ( bone resorption)
IL-2: secreted by T helper lymphocytes and helps to amplify the overall T cell
response
IL-3: secreted by activated T cells, mast cells, NK cells, eosinophils

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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

Stimulates differentiation of B cells into plasma cells


IL-12: main source is macrophages

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

Activates macrophages and NK cells, and suppresses Th2 cell activity


TNF-: secreted mainly by macrophages

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Notable functions of TNF-:


- Mediates septic shock
- Causes vascular leakage, induces leukocyte recruitment
- Helps form and maintain granulomas

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Type II Hypersensitivity
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Basic Sciences Immunology Immune Response

3 questions

Type 2 HSRs (type II (antibody-mediated) hypersensitivity reactions): IgM


and/or IgG autoantibodies bind fixed antigens in specific tissuesie, there
are no circulating immune complexes type 2 HSRs are usually tissue-specific
instead of systemic (vs. type 3 HSRs which involve circulating immune complexes
and are usually systemic)
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2 categories of pathogenesis in type 2 HSRs:
1) Cytotoxic: antibodies can bind and initiate cytotoxicity via a variety of
mechanisms, including:
- Opsonization and phagocytosis
- Complement-mediated inflammation and tissue damage
- Fc receptor-mediated inflammation and tissue damage (also known
as ADCC (antibody-dependent cell-mediated cytotoxicity))

2) Non-cytotoxic: antibodies can bind and interfere with normal functionfor


example:
- Myasthenia gravis: anti-ACh (acetylcholine) receptor antibodies bind postsynaptic
ACh receptors prevents ACh from binding postsynaptic ACh receptors + induces
downregulation of postsynaptic ACh receptors
- Graves disease: anti-TSH receptor antibodies bind and thereby
stimulate TSH receptors
- Pernicious anemia: anti-IF (intrinsic factor) antibodies bind and thereby prevent IF
from binding with vitamin B12 absorption of vitamin B12 in the ileum
Examples of Type II (antibody-mediated) hypersensitivity include:

1) ITP (idiopathic (immune) thrombocytopenic purpura, also known as


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autoimmune thrombocytopenic purpura): antibodies against platelet membrane
proteins (eg, GpIIb:IIIa integrin) opsonize platelets and/or activate complement
complement-mediated platelet lysis and/or phagocytosis by neutrophils and
macrophages bleeding due to quantitative platelet deficiency
2) Autoimmune hemolytic anemiafor example:
- Erythroblastosis fetalis (also known as hemolytic disease of the newborn)
- Transfusion reactions (eg, blood group (ABO, Rh, Kidd, Kell) incompatibility):
preformed antibodies in the recipients blood opsonize donor RBCs and/or activate
complement complement-mediated RBC lysis and/or rapid phagocytosis by
neutrophils and macrophages hemolysis, anemia
3) Pemphigus vulgaris: anti-desmosome antibodies (eg, IgG1 and/or IgG4
antibodies against desmoglein-1 and/or desmoglein-3) flaccid, easily ruptured
intraepidermal bullae + positive Nikolsky sign (gentle rubbing of unaffected skin
separation of epidermis)

4) Acute rheumatic fever: antibodies against streptococcal wall antigen


cross-react with joint and myocardial antigens arthritis, myocarditis
5) Graves disease: anti-TSH receptor antibodies bind and thereby
stimulate TSHreceptors hyperthyroidism
6) Goodpasture syndrome: anti-GBM (glomerular basement membrane)
antibodies react with the Goodpasture antigen (a peptide within the noncollagenous
domain of the 3 chain of type IV collagen) in GBMs and also cross-react with
pulmonary alveolar basement membranes complement activation releases C5a
(potent chemotactic factor) recruitment of neutrophils, which mediate tissue
damage by the lysosomal enzymes within their azurophilic granules nephritis
(hematuria) + pulmonary hemorrhage (hemoptysis)
7) Myasthenia gravis: anti-ACh (acetylcholine) receptor antibodies prevent
ACh from binding postsynaptic ACh receptors and also induce the downregulation of
postsynaptic ACh receptors paresis (muscle weakness), paralysis
9) Pernicious anemia: anti-IF (intrinsic factor) antibodies bind and thereby
prevent IF (produced by parietal cells lining the stomach) from binding with vitamin
B12 absorption of vitamin B12 in the ileum B12 deficiency
Megaloblastic macrocytic anemia: B12 deficiency cannot get methyl group off of
folate dTMP synthesis defect in DNA synthesis cannot make as many
cells as normal (hence anemia) + cannot mature/condense nuclei or cells (hence
megaloblastic macrocytic)
Neurologic deficits: B12 deficiency defect in propionate (odd-chained fatty acid)
metabolism defect in synthesis of CNS myelin subacute combined
degeneration due to demyelination of:
- Dorsal columns (cuneate and gracile nuclei and tracts) impaired
position/vibration sense (positive Romberg test)
- Lateral corticospinal tracts signs of upper motor lesion (hyperreflexia, muscle
tone, positive Babinski with toes upgoing/extending and fanning out upon stimulation
of plantar aspect of foot)
- Spinocerebellar tracts ataxic gait
Hemolytic disease of the newborn (erythroblastosis fetalis): transplacental transfer of
maternal anti-Rh IgG (usually anti-RhD) binds to Rh+ fetal RBCs fetal RBCs are
destroyed (relative hypoxia, altered cellular metabolism)

Prevention of erythroblastosis fetalis is required when the mother is Rh - and


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her fetus is Rh: administer anti-Rh antibody (RhoGAM) to the mother at 28 weeks
gestation and again within 1-2 days of delivery to neutralize fetal Rh antigens that

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
0

Hypersensitivity occurs when the body has an inappropriate, or exaggerated


inflammatory response to generally benign stimuli.
Common antigens include: pollen, dust, mold, mites, ragweed, animal danders as
well as food items such as peanut, chocolate and shellfish.
Initial antigenic exposure induces synthesis of IgE, which binds to the surface of
mast cells and basophils via its Fc portion.
Note: IL-4 from Th-2 cells induces the class switching from IgG IgE.

Re-exposure to same antigen crosslinking of surface bound


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IgE molecules degranulation of basophils and mast cells. This initiates
the immediate phase of the reaction.
Immediate Phase: Release of histamine, tryptase, kininogenase,
prostaglandins, platelet aggregating factor, and ECF-A. Since no products need to be
synthesized by the cell, this process is rapid.
Note: These mediators are responsible for the immediate edema, erythema and
pruritis that result after exposure.
While the initial phase is in progress, the cell also begins
synthesizing leukotrienes and their derivatives as a part of the late phase of the
reaction.
The products of the late phase reaction are inflammatory and attract neutrophils and
eosinophils.

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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Histamine: Preformed in granules of mast cells and basophils. Acts on the


post-capillary venules to cause vasodilation and increased capillary permeability.
Serotonin: Preformed in granules of platelets and mast cells. Released
during acute phase, and acts similarly to histamine vasodilation and increased
vascular permeability.
Leukotrienes: Synthesized on demand (i.e. not preformed). Increase
vascular permeability and are best known for their role in bronchoconstriction.
ECF-A (Eosinophil Chemotactic Factor of Anaphylaxis): Preformed in
granules of mast cells. Attracts eosinophils to the site of inflammation.

Eosinophils are recruited to the site of inflammation as a part of the late-phase


reaction. Once present, they release several mediators, among them arylsulfatase
and histaminase which can act to decrease the severity of inflammation.
However, LTC4 and PAF are also released which overall activate mast cells to further
release cytokines.

Thus, eosinophils are now believed to amplify and sustain the inflammatory
response, thus necessitating treatment with corticosteroids.

Note: Eosinophils contain a variety of preformed cytoplasmic granule mediators (e.g.


major basic protein and eosinophilic cationic protein) that can cause epithelial
damage
Atopic Disorders: type I hypersensitivity reactions that generally carry
a strong family history. They are generally associated with serum IgE.
Examples include: allergic rhinitis, asthma and eczema.

1) Allergic rhinitis (hay fever): most common form of atopy.

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Desensitization: Definitive treatment. Involves repeated subliminal doses to


allergens. This enables the synthesis of IgG, combines avidly with the repeat
exposure of circulating allergens and prevents activation of IgE-antigen induced
inflammatory mediators.
2) Urticaria: cutaneous form with vasodilation and increased vascular
permeability of the skin

3) Asthma: obstruction due to mucus secretion and smooth muscle


contraction surrounding bronchioles
Anaphylaxis: a severe, systemic reaction that occurs when the allergen-induced
mediators are released systemically. Can cause severe hypotension, shock and even
death.

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
0

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-

Cell Surface Proteins


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Basic Sciences Immunology Immune Response

6 questions
0

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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Type IV Hypersensitivity: Cell-mediated or delayed type response, sometimes


referred to as delayed type hypersensitivity (DTH). Initiated by antigen-activated T
cells (including both CD4and CD8 cells)

Cytotoxic T cells, monocytes, and macrophages cause direct tissue damage


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Involved in the pathogenesis of many infectious and autoimmune disease processes.
3 main types: granulomatous, tuberculin type, and contact response

Examples of disease processes mediated by type IV hypersensitivity:


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Type I Diabetes Mellitus
Multiple Sclerosis
Guillan-Barre Syndrome
Hashimoto's thyroiditis
Graft-versus-Host disease
PPD reaction in Mycobacterium tuberculosis
Contact dermatitis
Granulomatous reactions
1) Tuberculin test (PPD): injection of antigen Langerhans cells present the
antigen to previously sensitized T cells yields an indurated, erythematous lesion
Histologically, the inflammatory response occurs around the small vessels less
(perivascular cuffing)
2) Granulomatous reactions: occur if antigen persists in the tissues and continues
to stimulate host reactivity. IFN- promotes macrophage retention and monocyte
fusion epithelioid cell granuloma
3) Contact dermatitis: haptens (small-molecular-weight chemicals) or irritants are
deposited into the skin inflammation and blistering
Common agents causing contact dermatitis: nickel, dinitrochlorobenzene, less
rubber, poison ivy, and poison sumac

The hapten becomes antigenic when it combines with intradermal proteins as


carriers via NH3 or S-groupings

4) Rheumatoid Arthritis: There is a component of antigen/antibody complex


deposition involved in RA (thus some sources consider it to also be
Type III Hypersensitivity), however RA is generally classified as Type IV
Hypersensitivity because of the T-cell mediated inflammation.

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.

Innate vs. Adaptive Immunity


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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

1 question
0

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).

Innate immunity is maintained by a vast repertoire of serum proteins that less


recognize general classes of invading agents and which constantly sample the local
environment. This provides for a fast immune response; however the proteins do
not exhibit any memory in the case of recurrent infection.

The innate immune system involves:


- NK (natural killer) cells
- Phagocytes, neutrophils
- Dendritic cells
- Complement
Adaptive Immunity:

Involves memory: T and B cell receptors undergo somatic rearrangement less


(VDJrecombination) which are produced long after infection.
Response to infection is initially slow (often occurring after the innate
response). Response is faster upon repeat infection.

Primarily involves T-cells, B-cells and circulating antibodies.

Spleen
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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

9 questions

The spleen is a secondary lymphoid organ with roles in blood


filtration and microbial defense.
The spleen resides in the left upper quadrant (LQU), intraperotineal, along ribs 9,
10 and 11.
The spleen is derived, around the 6th week of development, from mesenchymal
cells of the dorsal mesentery. Despite its mesenchymal origin, the spleen still
shares blood supply with organs of the foregut. Specifically, the spleen receives
blood from the splenic artery, the largest branch of the celiac trunk.
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A posterior perforation of the stomach, typically due to an ulcer, may lead
to perforation of the splenic artery.

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.

The lymphoid nodules contain germinal centers, which are primarily


composed of B cells.
Between the white pulp and the red pulp is a marginal zone composed of antigen
presenting cells (APCs) and specialized B cells. The primary role of the marginal
zone is to trap antigens from circulation to present them to splenic
lymphocytes.
The red pulp is composed of the splenic cords of billroth and splenic (venous)
sinusoids. The splenic sinuses are engorged with blood, giving this area its red
color.

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).

After a splenectomy, there is a significant risk for infection with encapsulated


bacteria. Oftentimes patients will be prophylactically treated with antibiotics to
prevent such infection. In addition, the following can be observed on a blood smear:

Howell-Jolly bodies in RBCs

Target cells

Thrombocytosis

A useful for mnemonic to remember which organs are retroperitoneal is:

SAD PUCKER

Mnemonic

S - Suprarenal (adrenal) gland


A - aorta/IVC
D - duodenum (second and third part)
P - pancreas (except tail)
U - ureters
C - colon (ascending and descending)
K - kidneys
E - (o)esophagus
R - rectum

Immunoglobulins
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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

1 question
0

Five immunoglobulin classes: IgM, IgG, IgA, IgE, and IgD


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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

Igs on the surface of nave B cells: IgM, IgD


Igs on the surface of memory B cells: IgG, IgA, or IgE (but only one Ig class
per memory B cell)
Igs capable of mediating ADCC (antibody-dependent cell-mediated
cytotoxicity): IgG, IgE
IgE can only mediate ADCC in the one special case in which in the target is a
parasitic worm (e.g., an invasive helminth) in this case, the effector cell is an
eosinophil.
In IgG-mediated ADCC, the target cells are first bound by IgG effector cells may
then bind to the free Fc tail of IgG effectors release cytotoxic mediators (e.g.,
lytic enzymes, perforin, granzymes, tumor necrosis factor) to ultimately kill the target
cell. Note: phagocytosis is not involved in ADCC!
Effector cells capable of IgG-mediated ADCC all have Fc (membrane
receptors for the Fc region of IgG), and include:
- NK cells
- Neutrophils
- Monocytes and Macrophages
- Eosinophils

IgG is the only Ig capable of :


1) Crossing the placenta
2) Opsonization

To remember the most prevalent forms of Ig in serum, use the mnemonic


GAMmaglobulin:
- IgG = most common Ig in serum
- IgA = 2nd most common Ig in serum
- IgM = 3rd most common Ig in serum
IgG:
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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

In serum, IgA exists as a monomer.


In mucosal secretions, IgA exists dimer 2 IgAs held together by a J-chain (similar
to the J-chain in the pentameric form of IgM) 4 antigen binding sites.

After being produced by plasma cells within MALT (mucosal-associated


lymphoid tissues, e.g., tonsils, Peyers patches), dimeric IgA binds to receptors on
the basolateral surface of an epithelial cell, triggering endocytosis transepithelial
transport release ofsecretory IgA onto the mucosal surface
Note:
- secretory IgA = dimeric IgA (2 IgAs held together by a J-chain) + secretory piece
- secretory piece = part of the receptor on the basolateral surface of the epithelial cell
which mediated endocytosis, transepithelial transport, and release of IgA onto the
mucosal surface
- after release onto the mucosal surface, the secretory piece protects secretory IgA
against proteolytic cleavage

As the most abundant Ig class in mucosal secretions by far, it comes as no


surprise that the primary function of IgA = protective defense of the mucosa of
the respiratory, digestive, and urogenital systems against toxins and microbial
pathogens
IgM:

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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.

Splenectomy circulating IgM.


IgD:

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:

Before binding to antigen, IgE binds tightly to Fc receptors on basophils and


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mast cells thus, it is the least common Ig in serum.
Once bound to the Fc receptors on basophils and mast cells, binding of
cognate antigen (e.g., allergens) by IgE triggers release of cytokines and other
mediators involved in the allergic response this is a Type 1HSR (hypersensitivity
reaction).
During an infection with invasive helminths (e.g., Strongyloides, Trichinella,
Ascaris, Necator, Ancylostoma), IgE mediates an ADCC (antibody-dependent cellmediated cytotoxicity) response:
IgE binds to the surface of the helminth eosinophils (which have Fc receptors for
IgE, aka FcRs) bind to the free Fc tail of the IgE, triggering eosinophil
degranulation release of cytotoxic mediators (e.g., lytic enzymes, perforin,
granzymes, tumor necrosis factor) to try to kill the helminth.

Serum levels of IgE tend to rise during infections with invasive helminths (e.g.,
Strongyloides, Trichinella, Ascaris, Necator, Ancylostoma).
Immunoglobulin isotype, allotype, and idiotype:

Isotype (IgG, IgA, IgM, IgD, IgE):


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- determined by the primary sequence of amino acids in the constant region of the
heavy chain (which determines the 3-dimensional structure of the molecule)
- antigenic determinant that divides the antibodies into different types and subclasses
isotypes are shared across an entire species
Allotype (polymorphism):
- slight differences in the constant region of the heavy and light chains

- 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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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

8 questions
0

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

CD 19: co-receptor with CD21; involved in signal transduction during B cellless


activation
CD 20: function unknown
CD 21 (CR2, C3d receptor): co-receptor with CD19; involved in B-cell
activation. Is also the receptor for complement component C3d

EBV (Epstein-Barr virus) gains access into B cells via CD 21 infectious


heterophil-positive mononucleosis
Each B cell can only make Ig specific to one antigen

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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:

1) Existence of multiple allotypes of V, D, and J genes (inherited from parents)


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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

Once VDJ and VJ recombination are complete, allelic exclusion inactivates


one chromosome in a homologous pair ensures that only one Ig idiotype is
expressed in each B cell
T cell-dependent activation of a mature (nave) B cell (surface IgM+ and IgD+)
involves 3 steps:
1) B cell surface immunoglobulins (B cell receptors) are bound and cross- less
linked by their specific cognate antigen clustering of B cell receptors triggers
endocytosis of receptor-antigen complexes into the B cell cytoplasm
2) Endocytosed antigen is dissociated from the B-cell receptor and then
cross-linked toMHC class II peptides antigen-MHC II complexes are then inserted
into the B cell membrane and displayed on the B cell surface
3) TH (Helper T cells) recognize this MHC-complexed antigen and provide a
co-stimulatory signal.
The co-stimulatory signal is required for activation of B cells and differentiation into
plasma cells.
-B7 protein on B cell interacts with CD28 on Th cell activates Th cell
-CD40 protein on B cell interacts with CD40L (CD40 ligand) on Th cell activates
B cell.
There are two examples of T cell-independent activation of B cells:

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-

bound B cell surface molecules clustering of B cell receptors linked to the


mitogen-bound B cell surface molecules polyclonal T cell-independent
activation of B cells that do notrecognize the inciting mitogen. In other words, a
single mitogen can activate many different B cells with many different specificities,
none of which are specific for the mitogen!

Type 2: Some non-protein antigens like carbohydrates [e.g.,


the LPS(lipopolysaccharide) endotoxin in the cell wall of most gram-negative
bacteria] have repeating epitopes that can cross-link a large number of B cell
receptors at once clustering of B cell receptors antigen-specific T cellindependent activation of B cells that recognize the repeated epitope
Upon antigenic stimulation mature (nave) B cells may become either antibodyproducing plasma cells or memory B cells.
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Somatic Hypermutation (aka Affinity Maturation) (occurs in B cells
only, not in T cells):
- After antigen stimulation rapid clonal proliferation of B cells (which produce
antibodies against one particular antigen) naturally occurring mutations in this
rapid process yield antibodies with varying affinities for the antigen B cells which
produce antibodies with the highest antigen affinity are selected
- Note: this is the only change in idiotype that occurs after antigen stimulation
Following antigen-specific activation, mature (nave) B cells are able to
produce an immunoglobulin isotype other than IgM or IgD (e.g., IgG, IgA, or IgE)
by isotype switching, which is accomplished through irreversible genomic
recombination of heavy chain constant regions.

Primary vs. Secondary Lymphoid Organs


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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

3 questions
0

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.

Mature = immunocompetent = capable of mounting an immune responseless


following antigenic stimulation
Nave = not yet exposed to cognate antigen

Primary lymphoid organs: sites of lymphocyte birth and/or maturation via a


process that does not involve stimulation by foreign antigen (i.e., an antigenindependent process) mature nave lymphocytes
Normally, primary lymphoid organs do not contain lymphoid follicles.

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Primary lymphoid organs include:


1. Bone marrow
2. Thymus
Secondary lymphoid organs: sites of antigenic stimulation of mature nave
lymphocytes lymphocyte activation. This process is clearly antigendependent (i.e., stimulation byforeign antigen is required).

Normally, all secondary lymphoid organs have lymphoid follicles.

Secondary lymphoid organs include:


1. Lymph nodes
2. Spleen
3. MALT (mucosal-associated lymphoid tissue) e.g., tonsils, adenoid glands,
Peyers patches

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T cells
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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

1 question
0

T cell surface markers:

CD2 and CD3, which are important in signal transduction, are major markers
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of all peripheral T cells

The presence of CD4 defines T helper cells


The presence of CD8 defines cytotoxic T cells
Primary roles of 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:

Initial step: foreign body phagocytosis by an APC (antigen presenting cell).less


This is followed by two co-stimulatory signals.
First signal: Antigen presentation via MHC-II. This is recognized by
the TCR (T-cell receptor) of the T helper cell
Second signal: Interaction of B7 on the APC with CD28 on the T helper cell

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.

Second signal: IL-2 secreted by Th cells binds IL-2R on CD8+ cells


activation to kill the virus infected cell.

Thymus and T-cell Differentiation


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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

2 questions
0

The Thymus is the major site of T-Cell development

Functions to convert hematopoietic progenitor cells immature thymocytes


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T-cells
The entire organ is enclosed by an investing capsule. Just deep to the
capsule is the cortex. The medulla is the thymic center.
Formed by fusion of the ventral wings of the third branchial pouch
Cortex: dense with immature T-cells. It is the predominant site of positive
selection (selecting functional T-cells).
Medulla: pale-colored because it contains mature T-cells, epithelial reticular
cells, andHassalls corpuscles (remains of epithelial tubes which grow out from the
third branchial pouches).
It is the predominant site of negative selection (elimination of autoreactive T cells).

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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The earliest thymocytes found in the thymus are CD4-CD8- then


CD4CD8 thymocytes finally develop into either:
- CD4CD8-, also known simply as CD4 helper T cells, or Th cells; or
- CD4-CD8, also known simply as CD8 cytotoxic T cells, or CTLs.

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

CD8+ T cells develop into CTLs (cytotoxic T lymphocytes), which mainly


function to destroy:
- virus-infected cells
- tumor cells
- donor graft cells

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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.

Th2 cells coordinate a humoral (antibody) response to extracellular


pathogens (eg, helminths) and allergens:
1. Extracellular pathogens and allergens do not stimulate a strong innate immune
response involving macrophages and NK cells differentiation of pleuripotent Th0

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.

Th2 cells help B cells make antibodies:


- Th2 cells are essential for IgE production
- Th2 cells also help stimulate production of IgG and IgA

Lymph Node
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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

5 questions
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Lymph nodes are secondary lymphoid organs that perform 2 main functions:

1. Nonspecific filtration of lymph macrophages within lymph nodes may less


trap / destroy malignant cells, microorganisms (e.g., viruses, bacteria, fungi), debris
(e.g., anthracotic pigment).

2. Facilitates interaction between lymphocytes and APCs (antigen presenting


cells e.g., macrophages, dendritic cells) activation of lymphocytes (e.g., B cells,
T cells)
HEVs (high endothelial (postcapillary) venules) transport T- and B-cells from the
bloodstream to the lymph node paracortex:
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In the bloodstream, L-selectins on mature nave lymphocytes weakly bind to
addressins on endothelium
This weak interaction allows stronger integrin-mediated binding and
subsequent diapedesis
Lymphocytes leave the blood and are carried by HEVs into the paracortical
area of lymph nodes.

Guided by chemokine gradients, B-cells migrate to the cortex while T cells


primarily remain local within the paracortex.
Cortex: composed of lymphoid follicles (mostly B-cells within a loose network of
antigen-presenting follicular dendritic cells) as well as reticular cells, macrophages,
and some scattered CD4 helper T cells.
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Prior to antigenic stimulation, primary follicles are composed of small,


resting B cells

In response to antigenic stimulation, secondary follicles form. These contain


a pale germinal center (mainly activated, proliferating B cells) and a mantle zone
(both antigen-presenting B cells and T helper cells)
Paracortex: T-cell rich area that lies between the lymph node cortex and medulla.

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

2. Thymic aplasia or hypoplasia (e.g., DiGeorge syndrome) number of


circulating lymphocytes hypoplastic, smaller-than-normal paracortex due to lack
of lymphocyte influx
Medulla: consists of large blood vessels, medullary cords, and medullary sinuses

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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

Medullary sinuses are endothelial-lined lymphatic spaces that collect lymph


destined for the efferent lymphatics. They contain macrophages and reticular cells.
Key Lymphatic Drainages

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

Superficial thigh superficial inguinal nodes


Lateral dorsal foot popliteal nodes
The right lymphatic duct drains the right arm and the right half of the head

The thoracic duct begins anterior to L1 or L2 adjacent to the aorta.

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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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

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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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The variable regions are responsible for binding antigen.


The constant regions help the antibody do its usual biological functions such
as activate complement and bind to various cell surface receptors.
Heavy chain is part of both Fc (constant) and Fab (antigen binding) regions
A specific amino acid sequence on the heavy chains differentiates the Ig
classes (IgG, IgA, IgM, IgE, IgD)
The C-terminal region of the Fc portion of IgG and IgM binds complement. The Fc
portion of IgA/G/E activates effector cells.

Light Chain

L chains are either (kappa) or (lambda). Either one can be found in anyless
of
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).

HLA & MHC


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Basic Sciences Immunology Lymphoid Organs and Lymphocytes

1 question
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HLA: Human Leukocyte Antigen classes, consists of three classes of molecules


(Major Histocompatibility I, II, and III)

Discriminates between self and nonself. Also involved in antigen presentation


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to T cells by self-MHC restriction (antigens can only be presented to T cells with the
same HLA type).

Specific HLAs are associated with various immunologic disorders and


susceptibility to infectious agents
Major Histocompatibility Complex-I (MHC-I)

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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.

2 microglobulin is necessary for cell surface expression of MHC-I. Note: 2


microglobulin is not expressed on RBCs
Major Histocompatibility Complex-II (MHC-II)

Primarily found on cell membranes of APCs (antigen presenting cells):


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dendritic cells, macrophages, activated B cells. Also found on activated T cells.

In contrast to MHC-I proteins, MHC-II proteins present antigens


from extracellularorganisms that have been phagocytosed and digested by the
APCs.
Encoded by the following Human Leukocyte Antigen (HLA) genes: HLADR, HLA-DP, HLA-DQ
After processing the antigen, macrophages typically present fragments
via class II MHCproteins, which bind to T-cell receptors on the surface of CD4+ Th
cells.

This MHC-II presentation of antigen activates the Th cell, which release:


-IL-2 Tc cell activation cell death.
-IL-4 and IL-5 B cell activation differentiation into plasma cell OR activation of
appropriate memory B cell specific for that particular antigenic fragment.

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-)

This region also encodes for 21-hydroxylase, a key enzyme in glucocorticoid


synthesis