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93
MOLECULAR BIOLOGY OF THE IMMUNE SYSTEM
PROPERTIES OF IMMUNOGLOBULINS
TABLE
13-1
Property
IgM
IgD
IgG
IgE
IgA
H chain
ε
L chain
or
or
or
or
or
Other chains
J chain
None
None
None
J chain secretory
piece (SP)
Structural
Monomer:
Monomer:
Monomer:
Monomer:
Monomer:
designation
2
2
or
2
2
2
2
or
2
2
2
2
or
2
2
ε
2
2
or
ε
2
2
2
2
or
2
2
Pentamer: (
2
Dimer: (
2
2
)
2
2
)
5
or or
(
2
2
)
2
(
2
2
)
5
Dimer with SP:
(
2
2
)
2
or
(
2
2
)
2
SP
Carbohydrate (%)
15
18
4
18
10
Molecular weight
Monomer:
Monomer:
Monomer:
Monomer:
Monomer:
(kilodaltons)
180 kDa
184 kDa
150 kDa
188 kDa
160 kDa
Pentamer:
Dimer: 318 kDa
950 kDa
Dimer with SP:
380 kDa
Serum 150
3
50–900
0.03
50–300
concentration
(mg%)
Serum half-life
5
2.5
8–23
3
6
(days)
Binds to F
C
receptor
Activates
complement
Crosses placenta
No
No
Yes
No
No
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94
CHAPTER 13
A. T-CELL RECEPTOR (TCR) STRUCTURE (Figure
13-3). A TCR consists of two protein subunits:
1
(alpha) chain and 1 (beta) chain or 1
(gamma) chain and 1
(delta) chain.
1.
The
chain.
The
chain gene segments
are located on chromosome 14 and
include 100 variable segments (V
), 100
joining segments (J
), and 1 constant
segment (C
), resembling
the im-
munoglobulin light chains. The V
, J
, C
gene segments undergo gene rearrange-
ment to contribute to TCR diversity.
● Figure 13-3 T Cell Receptor Structure.
2.
The
chain.
The
chain gene segments are located on chromosome 7 and in-
clude
100 variable segments (V
), 2 diversity segments (D
), 15 joining seg-
ments (J
), and 2 constant segments (C
), resembling the immunoglobulin heavy
chains. The V
, D
, J
, C
gene segments undergo gene rearrangement to con-
tribute to TCR diversity.
3.
The
chain.
The
chain gene segments are located on chromosome 7 and include
variable segments (V
), joining segments (J
), or constant segments (C
), resem-
bling the immunoglobulin light chains. The V
, J
, C
gene segments undergo gene
rearrangement to contribute to TCR diversity.
4.
The
chain.
The
chain gene segments are located on chromosome 14 and in-
clude
4 variable segments (V
), 2 diversity segments (D
), 100 joining seg-
ments (J
), and 1 constant segment (C
), resembling the immunoglobulin heavy
chains. The V
, D
, J
, C
gene segments undergo gene rearrangement to contribute
to TCR diversity.
5.
The diagram demonstrates TCR structure. The location of the
chain, chain,
chain, and chain gene segments on chromosomes 7 and 14 are indicated.
The
, , , and chain gene segments are organized into various V, D, J,
and C gene segments which undergo gene rearrangement, transcription, splic-
ing, and translation to form a TCR. A TCR consists of either a
chain and
chain (
) or a chain and chain (). V variable, D diversity, J
joining, C
constant.
B. TCR DIVERSITY (Figure 13-4)
1.
The fundamental principles of gene re-
arrangement already explained for im-
munoglobulins also apply to the diversity
found in the TCR.
2.
The diagram demonstrates TCR diversity.
The gene rearrangement using
chain
gene segments as an example is shown.
The un-rearranged
chain gene segments
consisting of 100 V
segments, 2 D
seg-
ments, 15 J
segments, and 2 C
segments
undergo gene rearrangement whereby
particular segments (e.g., V
49
, D
1
, J
9
, and
C
1
) are brought together while intervening gene segments are excised and de-
graded. The rearranged
chain gene segments undergo transcription to form a
● Figure 13-4 T Cell Receptor Diversity.
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95
MOLECULAR BIOLOGY OF THE IMMUNE SYSTEM
primary RNA transcript. The primary RNA transcript undergoes splicing to form
mRNA (V
49
, D
1
, J
9
, and C
1
). The mRNA undergoes translation to form a
chain
polypeptide with a unique amino acid sequence that corresponds to the V
49
, D
1
,
J
9
, and C
1
gene segment codons. Black segments of the TCR represent the portion
that binds antigen.
A. X-LINKED INFANTILE AGAMMAGLOBULINEMIA (XLA; BRUTON)
1.
XLA is caused by a mutation in the BTK gene (Bruton tyrosine kinase) located on
chromosome X (Xq22) which encodes for a tyrosine kinase involved in the dif-
ferentiation of pre-B cells into mature B cells.
2.
This disorder is due to the inability of pre-B cells to differentiate into mature B
cells due to the failure of V
H
gene segments to undergo gene rearrangement.
3.
Clinical signs include the following: occurs only in male infants, becomes appar-
ent at 5–6 months of age, recurrent bacterial otitis media, septicemia, pneumonia,
arthritis, meningitis, and dermatitis (most commonly due to Haemophilus influenza
and Streptococcus pneumonia).
4.
Laboratory findings include an absence of all classes of immunoglobulins within
the serum and
1% CD19
B cells or CD20
B cells.
B. SEVERE COMBINED IMMUNE DEFICIENCY (SCID). The SCID syndromes are a het-
erogeneous group of disorders due to a defect in the development and function of B
cells and T cells. In some cases, the defect causes only T-cell dysfunction, but im-
munoglobulin production may also be compromised because B cells require signals
from T cells to produce an effective immunoglobulin response. SCID presents in the
early newborn period but can be delayed several months because maternally derived
immunoglobulins provide early immune protection.
1.
Adenosine deaminase deficiency (ADA; ADA
SCID)
a.
ADA is caused by a mutation in the ADA gene located on chromosome 20q12-
q13.11 which encodes for adenosine deaminase which catalyzes the deami-
nation of adenosine and deoxyadenosine into inosine and deoxyinosine, re-
spectively. Inosine and deoxyinosine are converted to waste products and
excreted.
b.
A lack of adenosine deaminase activity results in the accumulation of adeno-
sine and deoxyadenosine which are particularly toxic to T cells.
c.
Clinical signs include recurrent severe infections, chronic mucocutaneous
candidiasis, infections with common viral pathogens (e.g., respiratory syncy-
tial virus, varicella zoster, herpes simplex, measles, influenza, parainfluenza)
are frequently fatal, susceptibility to opportunistic infections (e.g., Pneumocys-
tis carinii), attenuated vaccine organisms (e.g., oral polio vaccine virus) may
cause fatal infection, chronic diarrhea, and failure to thrive. The only treat-
ment for all forms of SCID is stem cell transplantation.
d.
Laboratory findings include severe T-cell deficiency with low numbers of CD3
and CD4
T cells, poor in vitro lymphocyte mitogenic and antigenic responses,
and absent mixed lymphocyte reactions.
C. 22Q11.2 DELETION SYNDROME (DS; CONGENITAL THYMIC APLASIA; DIGE-
ORGE SYNDROME)
1.
DS is caused by a microdeletion of the DiGeorge chromosomal critical region
on chromosome 22q11.2. Approximately 90% of DS individuals have a de novo
deletion.
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96
CHAPTER 13
2.
The TBX1 gene which encodes for T-box transcription factor TBX10 protein is
most likely one of the genes that is deleted in DS and results in some of the clini-
cal features of DS.
3.
DS encompasses the phenotypes previously called DiGeorge syndrome, velocar-
diofacial syndrome, conotruncal anomaly face syndrome, Opitz g/BBB syndrome,
and Cayler cardiofacial syndrome.
4.
These infants have no T cells and many infants even fail to mount an immuno-
globulin response which requires CD4
helper T cells.
5.
Clinical signs include facial anomalies resembling first arch syndrome (mi-
crognathia, low-set ears) due to abnormal neural crest cell migration, cardio-
vascular anomalies due to abnormal neural crest cell migration during forma-
tion of the aorticopulmonary septum (e.g., Tetralogy of Fallot), velopharyngeal
incompetence, cleft palate, immunodeficiency due to thymic hypoplasia,
hypocalcemia due to parathyroid hypoplasia, and embryological formation of
pharyngeal pouches 3 and 4 fail to differentiate into the thymus and parathy-
roid glands.
Disorders of Phagocytic Function
A. MYELOPEROXIDASE DEFICIENCY (MPO)
1.
MPO (a relatively benign immunodeficiency) is caused by a mutation in the MPO
gene located on chromosome 17q23 which encodes for myeloperoxidase.
2.
Myeloperoxidase catalyzes the conversion of H
2
O
2
and chloride ion (Cl
) into
hypochlorous acid (i.e., bleach).
3.
MPO is most commonly caused by a missense mutation which results in a normal
arginine S tryptophan substitution at position 569 (R569W).
4.
Myeloperoxidase is synthesized by neutrophils and macrophages, packaged in en-
dolysosomes (or azurophilic granules), and released into phagolysosomes or the
extracellular space.
5.
Clinical signs: most individuals have no increased frequency of infections; if infec-
tions due occur, they are usually fungal in nature due to Candida albicans or Can-
dida tropicalis.
B. CHEDIAK-HIGASHI SYNDROME (CHS)
1.
CHS is a rare childhood autosomal recessive genetic disorder caused by a muta-
tion in the CHS1 gene located on chromosome 1q42.1–42.2 which encodes for
the CHS protein.
2.
The CHS protein is a trafficking regulator protein which is involved in the forma-
tion, fusion, or trafficking of storage/secretory granules in various cell types (e.g.,
lysosomes in neutrophils and other leukocytes, dense bodies of platelets, and
melanosomes in melanocytes).
3.
Clinical signs include recurrent pyogenic infections of the respiratory tract and
skin; severe gingivitis; oral mucosa ulceration; partial oculocutaneous albinism;
neurological disturbances (e.g., photophobia, nystagmus, peripheral neuropathy,
spinocerebellar degeneration, and seizures); accelerated phase involves wide-
spread infiltration of lymphocytes and histiocytes into the liver, spleen, and lymph
nodes; and few patients live to adulthood.
4.
Laboratory findings include neutrophils contain markedly abnormal giant cyto-
plasmic granules which are formed by the abnormal fusion of endolysosomes with
endosomes.
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97
MOLECULAR BIOLOGY OF THE IMMUNE SYSTEM
A. SYSTEMIC LUPUS ERYTHEMATOUS. See Chapter 6VA.
B. RHEUMATOID ARTHRITIS (RA; Figure 13-5)
1.
RA is a chronic, systemic, peripheral polyarthritis of unknown causes that typi-
cally leads to deformity and destruction of joints due to erosion of cartilage and
bone.
2.
RA has an association with major histo-
compatibility complex (MHC) Class II
genes located on chromosome 6. The as-
sociation becomes better defined when
the HLA-DRB1 allele (MHC, Class II, DR
beta 1) is evaluated because it appears that
this allele is involved in MHC Class II
binding antigenic peptides and presented
them to CD4
T cells.
3.
All of the associated alleles have in com-
mon a shared epitope involving amino
acids 67–74. Within this shared epitope, a
sequence of arginine, alanine, and alanine
at position 72–74 (RAA 72–74) appears to
account for the majority of increased risk
of RA.
4.
Clinical signs include insidious onset;
morning stiffness present for at least 1
hour; pain, stiffness and swelling of three
or more joints; swelling of wrist,
● Figure 13-5 Rheumatoid Arthritis.
metacarpophalangeal or proximal interphalangeal joints; symmetric joint
swelling; usually progresses from the peripheral to proximal joints; rheumatoid
subcutaneous nodules; may lead to destruction of the joints due to erosion of
bone and cartilage; synovial thickening may be detected by a “boggy” feel to the
swollen joint.
5.
Laboratory findings include anti-CCP antibodies (citrulline-containing pro-
teins).
6.
The top photograph shows the hands of a patient with advanced RA. Note the
swelling of the metacarpal phalangeal joints and classic ulnar deviation of the fin-
gers. The bottom photograph shows a rheumatoid nodule on a finger.
Organ-Specific Autoimmune Disorders
A. BLOOD DISORDERS. Monoclonal gammopathies refer to a group of neoplastic dis-
eases involving the abnormal proliferation of B cells and plasma cells resulting in ex-
cessive production of immunoglobulins or immunoglobulin chains.
1.
Multiple myeloma (MM; Figure 13-6)
a.
MM is most commonly caused by reciprocal translocation between band q32
on chromosome 14 containing the immunoglobulin heavy chain gene and the
following:
i.
Band p16 on chromosome 4 containing the FGF (fibroblast growth factor)
receptor 3 gene [t(14;4) (q32;p16)].
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