Medical Genetics
15 免疫缺陷
immunodeficiency
Medical Genetics
The immune system is a network
of interacting cellular and soluble
components,Its function is to
distinguish entities within the body
as "self" or "nonself" and to eliminate
those that are nonself,
Medical Genetics
Microorganisms are the principal
nonself entities,but neoplasms,
transplants,and certain foreign
substances (eg,some toxins) are also
important,To accomplish its tasks,the
immune system has evolved two
mechanisms,nonspecific immunity and
specific immunity,which are linked to and
influence each other,
Medical Genetics
Nonspecific (Innate) Immunity
This type of immunity is older
phylogenetically,is present at birth,does
not require a previous encounter with the
offending substance,and does not develop
memory,Innate immunity includes
barriers,such as the skin,and chemical
protection,such as gastric acid,
Medical Genetics
There are two cellular components,
(1)the phagocytic system,whose function is
to ingest and digest invading
microorganisms,and
(2) natural killer (NK) cells,whose function
is to kill some tumors,microorganisms,
and virally infected cells,The soluble
components consist of complement
proteins,acute phase reactants,and
cytokines,
Medical Genetics
Specific (Adaptive) Immunity
Specific immunity has the
hallmarks of learning,adaptability,
and memory,The cellular component
is the lymphocyte,and
immunoglobulins (Igs) are the
soluble component,
Medical Genetics
Immunodeficiency diseases,A
group of diverse conditions caused by
one or more immune system defects
and characterized clinically by
increased susceptibility to infections
with consequent severe,acute,
recurrent,or chronic disease,
Medical Genetics
An immunodeficiency disorder
should be considered in anyone with
infections that are unusually frequent,
severe,and resistant; without a
symptom-free interval; from an
unusual organism; or with
unexpected or severe complications,
Medical Genetics
Since immunodeficiency
disorders are relatively uncommon,
other disorders leading to recurrent
infection should be considered first,
If these disorders can be excluded,a
defect in host defense should be
suspected,
Medical Genetics
DISORDERS WITH INCREASED SUSCEPTIBILITY
TO UNUSUAL INFECTIONS
Medical Genetics
1,General
Immunodeficiencies may be
primary or secondary,Primary
immunodeficiency is classified into
four main groups depending on
which component of the immune
system is deficient,B cells,T cells,
phagocytic cells,or complement,
Medical Genetics
Over 70 primary
immunodeficiencies have been
described,and considerable
heterogeneity may exist within each
disorder,
Medical Genetics
CLASSIFICATION,INHERITANCE,AND ASSOCIATED FEATURES
OF THE PRIMARY IMMUNODEFICIENCY DISORDERS
Medical Genetics
Medical Genetics
Medical Genetics
2,Etiology
Immunodeficiency has no
common cause,although a single
gene defect is often implicated,
Medical Genetics
The defect can lead to a missing
enzyme (eg,adenosine deaminase
deficiency),a missing protein (eg,
complement component deficiencies),
or developmental arrest at a specific
differential stage (eg,pre-B-cell
arrest in X-linked
agammaglobulinemia),
Medical Genetics
Chromosome locations of the
defective genes have been identified
for many of the primary
immunodeficiencies,
Medical Genetics
In certain illnesses,intrauterine
events may be implicated (eg,
maternal alcoholism in some cases of
DiGeorge anomaly); in others,drug
ingestion may be implicated (eg,
phenytoin in IgA deficiency),The
exact biologic abnormality in most of
the illnesses is unknown,
Medical Genetics
3,Symptoms and Signs
Most manifestations of
immunodeficiency result from
frequent infections,usually beginning
with recurrent respiratory infections,
Medical Genetics
Infection of the skin and mucous
membranes also is common,Resistant
thrush may be the first sign of T-cell
immunodeficiency,Oral ulcers and
periodontitis also are noted,particularly in
granulocytic deficiencies,Conjunctivitis
occurs in many antibody-deficient adults,
Pyoderma,severe warts,alopecia,eczema,
and telangiectasia are common,
Medical Genetics
Common symptoms include
diarrhea,malabsorption,and failure
to thrive,The diarrhea usually is
noninfectious but may be associated
with Giardia lamblia,rotavirus,
cytomegalovirus,or Cryptosporidium,
In some patients,the diarrhea may
be exudative with loss of serum
proteins and lymphocytes,
Medical Genetics
Less common manifestations of
immunodeficiency include
hematologic abnormalities
(autoimmune hemolytic anemia,
leukopenia,thrombocytopenia),
autoimmune phenomena (vasculitis,
arthritis,endocrinopathies),and CNS
problems (eg,chronic encephalitis,
slow development,seizures),
Medical Genetics
4,Diagnosis
A family history should be
obtained,If there is a history of early
death,similar disease,autoimmune
illness,allergy,early malignancy,or
consanguinity,then a pedigree chart
will help identify a hereditary pattern,
Medical Genetics
? The type of infection
? The age of onset
? physical examination
? Laboratory Tests
Medical Genetics
6.Specific Immunodeficiencies
A,Transient hypo-
gammaglobulinemia of infancy
A self-limited antibody deficiency
of both sexes,with onset at age 3 to
6 mo,persisting usually for 6 to 18
mo,
Medical Genetics
Sometimes there is an associated
increased frequency of infection,The
disorder results from a delay in the
onset of Ig synthesis despite normal
numbers of B cells,T helper cells
may be reduced,Premature infants
are especially at risk because of
lower levels of transplacental IgG at
birth,The disorder is not familial,
Medical Genetics
B,X-Linked agammaglobulinemia
Bruton's Agammaglobulinemia
Congenital Agammaglobulinemia
Medical Genetics
Panhypogammaglobulinemia of
male infants characterized by levels
of IgG < 100 mg/dL and other Ig
levels low or absent,low or absent B
cells,intact cellular immunity,and
onset of infections sometime after
age 6 mo,when maternal antibodies
disappear,
Medical Genetics
These infants have recurrent
pyogenic infections of the lungs,
sinuses,and bones with such
organisms as pneumococcus,
haemophilus,and streptococcus,
Medical Genetics
They also are susceptible to
vaccine-induced poliovirus infection
and chronic echovirus encephalitis,
Some infants have arthritis that
disappears with IG therapy,X-linked
inheritance is proved in about 20%
of cases,
Medical Genetics
Medical Genetics
A defect of the Btk (Bruton's
tyrosine kinase) gene at Xq22
prevents differentiation of pre-B cells
to B cells,Different variants of the
defective gene exist in each kindred,
Medical Genetics
Treatment
Lifelong IG given IM or IV in the lowest
dose that prevents recurrent infection is
essential,Prompt,adequate antibiotic
administration with each infection is crucial;
continuous antibiotics are sometimes
indicated,Despite these measures,many
patients develop persistent sinusitis,
bronchitis,and bronchiectasis,
Susceptibility to malignancy is increased,
Medical Genetics
C,Hyper-IgM immunodeficiency
A congenital,usually X-linked
immunodeficiency characterized by
elevated levels of IgM,decreased
levels of IgG and IgA,intermittent
neutropenia,normal B-cell levels,
and susceptibility to infection,
Medical Genetics
Lymphadenopathy and
autoimmunity may be present,
Susceptibility to major gram-positive
pathogens and opportunistic
infections is increased,Most patients
(> 70%) develop chronic liver
disease by age 30,
Medical Genetics
This infant with X-linked immunodeficiency with
hyperimmunoglobulin M (XHIM) developed severe diarrhea and
hypoproteinemia,
Medical Genetics
The immunologic defect in the X-
linked form is a deficiency of T cell
gp39,the ligand for CD40 on B cells
that induces switching from IgM to
IgA,IgG,and IgE,The mutated gene
has been identified at Xq27,
Medical Genetics
Treatment
Treatment is similar to that of X-
linked agammaglobulinemia,
Granulocyte colony-stimulating factor
can be used for neutropenia,Stem
cell transplantation has been
successful in a few cases,
Medical Genetics
D,DiGEORGE anomaly
Thymic Hypoplasia
Third Pharyngeal Pouch Syndrome
Fourth Pharyngeal Pouch Syndrome
Medical Genetics
A congenital immunodeficiency
characterized pathologically by
absence or hypoplasia of the thymus
and parathyroid glands and
immunologically by partial or
complete T-cell immunodeficiency
but normal or near-normal B-cell
immunity,
Medical Genetics
Affected infants have low-set
ears,midline facial clefts,a small
receding mandible,hypertelorism,a
shortened philtrum,and congenital
heart disease,Tetany appears within
24 to 48 h of life,Both sexes are
equally affected,and familial cases
are uncommon,
Medical Genetics
Abnormalities of chromosome
22q (eg,deletion or monosomy) can
be identified in 90% of cases,There
seems to be an interruption of
normal development of pharyngeal
pouch structures near the 8th wk of
gestation,
Medical Genetics
Treatment
Bone marrow transplantation has
been successful,Some success has
been achieved with fetal thymus
transplants,The severity of the heart
disease often determines the
eventual prognosis,Partial deficiency
is compatible with prolonged survival,
Medical Genetics
E,Combined immunodeficiency
A group of disorders characterized
by congenital and usually hereditary
deficiency of both B- and T-cell
systems,lymphoid aplasia,and
thymic dysplasia,
Medical Genetics
Medical Genetics
Medical Genetics
The combined immunodeficiencies
include severe combined
immunodeficiency,Swiss
agammaglobulinemia,combined
immunodeficiency with adenosine
deaminase or nucleoside
phosphorylase deficiency,and
combined immunodeficiency with
immunoglobulins (Nezelof syndrome),
Medical Genetics
Most patients have an early
onset (within 3 mo of life) of
infection with thrush,pneumonia,
and diarrhea,If left untreated,most
die before age 2,Most patients have
profound deficiency of B cells and Igs,
Medical Genetics
The following are characteristic,
lymphopenia,low or absent T-cell
levels,poor proliferative response to
mitogens,cutaneous anergy,an
absent thymic shadow,and
diminished lymphoid tissue,
Pneumocystis pneumonia and other
opportunistic infections are common,
Medical Genetics
About 1/2 of patients with an
autosomal recessive inheritance have
adenosine deaminase (ADA)
deficiency,a purine salvage
pathway enzyme that converts
adenosine and deoxyadenosine to
inosine and deoxyinosine,
respectively,
Medical Genetics
ADA deficiency results in
elevated quantities of
deoxyadenosine triphosphate (dATP),
which inhibits DNA synthesis,ADA-
deficient patients may be normal at
birth but develop progressive
immunologic impairment as dATP
accumulates,
Medical Genetics
Treatment
Treatment with IG and antibiotics is
indicated but not curative,Treatment of
choice for all variants is stem cell
transplantation,Patients with ADA
deficiency have been treated successfully
with polyethylene glycol conjugated to
bovine ADA (PEG-ADA),IL-2-deficient
patients have been treated with
recombinant human IL-2,Gene therapy
has been used with some success in ADA
deficiency,
15 免疫缺陷
immunodeficiency
Medical Genetics
The immune system is a network
of interacting cellular and soluble
components,Its function is to
distinguish entities within the body
as "self" or "nonself" and to eliminate
those that are nonself,
Medical Genetics
Microorganisms are the principal
nonself entities,but neoplasms,
transplants,and certain foreign
substances (eg,some toxins) are also
important,To accomplish its tasks,the
immune system has evolved two
mechanisms,nonspecific immunity and
specific immunity,which are linked to and
influence each other,
Medical Genetics
Nonspecific (Innate) Immunity
This type of immunity is older
phylogenetically,is present at birth,does
not require a previous encounter with the
offending substance,and does not develop
memory,Innate immunity includes
barriers,such as the skin,and chemical
protection,such as gastric acid,
Medical Genetics
There are two cellular components,
(1)the phagocytic system,whose function is
to ingest and digest invading
microorganisms,and
(2) natural killer (NK) cells,whose function
is to kill some tumors,microorganisms,
and virally infected cells,The soluble
components consist of complement
proteins,acute phase reactants,and
cytokines,
Medical Genetics
Specific (Adaptive) Immunity
Specific immunity has the
hallmarks of learning,adaptability,
and memory,The cellular component
is the lymphocyte,and
immunoglobulins (Igs) are the
soluble component,
Medical Genetics
Immunodeficiency diseases,A
group of diverse conditions caused by
one or more immune system defects
and characterized clinically by
increased susceptibility to infections
with consequent severe,acute,
recurrent,or chronic disease,
Medical Genetics
An immunodeficiency disorder
should be considered in anyone with
infections that are unusually frequent,
severe,and resistant; without a
symptom-free interval; from an
unusual organism; or with
unexpected or severe complications,
Medical Genetics
Since immunodeficiency
disorders are relatively uncommon,
other disorders leading to recurrent
infection should be considered first,
If these disorders can be excluded,a
defect in host defense should be
suspected,
Medical Genetics
DISORDERS WITH INCREASED SUSCEPTIBILITY
TO UNUSUAL INFECTIONS
Medical Genetics
1,General
Immunodeficiencies may be
primary or secondary,Primary
immunodeficiency is classified into
four main groups depending on
which component of the immune
system is deficient,B cells,T cells,
phagocytic cells,or complement,
Medical Genetics
Over 70 primary
immunodeficiencies have been
described,and considerable
heterogeneity may exist within each
disorder,
Medical Genetics
CLASSIFICATION,INHERITANCE,AND ASSOCIATED FEATURES
OF THE PRIMARY IMMUNODEFICIENCY DISORDERS
Medical Genetics
Medical Genetics
Medical Genetics
2,Etiology
Immunodeficiency has no
common cause,although a single
gene defect is often implicated,
Medical Genetics
The defect can lead to a missing
enzyme (eg,adenosine deaminase
deficiency),a missing protein (eg,
complement component deficiencies),
or developmental arrest at a specific
differential stage (eg,pre-B-cell
arrest in X-linked
agammaglobulinemia),
Medical Genetics
Chromosome locations of the
defective genes have been identified
for many of the primary
immunodeficiencies,
Medical Genetics
In certain illnesses,intrauterine
events may be implicated (eg,
maternal alcoholism in some cases of
DiGeorge anomaly); in others,drug
ingestion may be implicated (eg,
phenytoin in IgA deficiency),The
exact biologic abnormality in most of
the illnesses is unknown,
Medical Genetics
3,Symptoms and Signs
Most manifestations of
immunodeficiency result from
frequent infections,usually beginning
with recurrent respiratory infections,
Medical Genetics
Infection of the skin and mucous
membranes also is common,Resistant
thrush may be the first sign of T-cell
immunodeficiency,Oral ulcers and
periodontitis also are noted,particularly in
granulocytic deficiencies,Conjunctivitis
occurs in many antibody-deficient adults,
Pyoderma,severe warts,alopecia,eczema,
and telangiectasia are common,
Medical Genetics
Common symptoms include
diarrhea,malabsorption,and failure
to thrive,The diarrhea usually is
noninfectious but may be associated
with Giardia lamblia,rotavirus,
cytomegalovirus,or Cryptosporidium,
In some patients,the diarrhea may
be exudative with loss of serum
proteins and lymphocytes,
Medical Genetics
Less common manifestations of
immunodeficiency include
hematologic abnormalities
(autoimmune hemolytic anemia,
leukopenia,thrombocytopenia),
autoimmune phenomena (vasculitis,
arthritis,endocrinopathies),and CNS
problems (eg,chronic encephalitis,
slow development,seizures),
Medical Genetics
4,Diagnosis
A family history should be
obtained,If there is a history of early
death,similar disease,autoimmune
illness,allergy,early malignancy,or
consanguinity,then a pedigree chart
will help identify a hereditary pattern,
Medical Genetics
? The type of infection
? The age of onset
? physical examination
? Laboratory Tests
Medical Genetics
6.Specific Immunodeficiencies
A,Transient hypo-
gammaglobulinemia of infancy
A self-limited antibody deficiency
of both sexes,with onset at age 3 to
6 mo,persisting usually for 6 to 18
mo,
Medical Genetics
Sometimes there is an associated
increased frequency of infection,The
disorder results from a delay in the
onset of Ig synthesis despite normal
numbers of B cells,T helper cells
may be reduced,Premature infants
are especially at risk because of
lower levels of transplacental IgG at
birth,The disorder is not familial,
Medical Genetics
B,X-Linked agammaglobulinemia
Bruton's Agammaglobulinemia
Congenital Agammaglobulinemia
Medical Genetics
Panhypogammaglobulinemia of
male infants characterized by levels
of IgG < 100 mg/dL and other Ig
levels low or absent,low or absent B
cells,intact cellular immunity,and
onset of infections sometime after
age 6 mo,when maternal antibodies
disappear,
Medical Genetics
These infants have recurrent
pyogenic infections of the lungs,
sinuses,and bones with such
organisms as pneumococcus,
haemophilus,and streptococcus,
Medical Genetics
They also are susceptible to
vaccine-induced poliovirus infection
and chronic echovirus encephalitis,
Some infants have arthritis that
disappears with IG therapy,X-linked
inheritance is proved in about 20%
of cases,
Medical Genetics
Medical Genetics
A defect of the Btk (Bruton's
tyrosine kinase) gene at Xq22
prevents differentiation of pre-B cells
to B cells,Different variants of the
defective gene exist in each kindred,
Medical Genetics
Treatment
Lifelong IG given IM or IV in the lowest
dose that prevents recurrent infection is
essential,Prompt,adequate antibiotic
administration with each infection is crucial;
continuous antibiotics are sometimes
indicated,Despite these measures,many
patients develop persistent sinusitis,
bronchitis,and bronchiectasis,
Susceptibility to malignancy is increased,
Medical Genetics
C,Hyper-IgM immunodeficiency
A congenital,usually X-linked
immunodeficiency characterized by
elevated levels of IgM,decreased
levels of IgG and IgA,intermittent
neutropenia,normal B-cell levels,
and susceptibility to infection,
Medical Genetics
Lymphadenopathy and
autoimmunity may be present,
Susceptibility to major gram-positive
pathogens and opportunistic
infections is increased,Most patients
(> 70%) develop chronic liver
disease by age 30,
Medical Genetics
This infant with X-linked immunodeficiency with
hyperimmunoglobulin M (XHIM) developed severe diarrhea and
hypoproteinemia,
Medical Genetics
The immunologic defect in the X-
linked form is a deficiency of T cell
gp39,the ligand for CD40 on B cells
that induces switching from IgM to
IgA,IgG,and IgE,The mutated gene
has been identified at Xq27,
Medical Genetics
Treatment
Treatment is similar to that of X-
linked agammaglobulinemia,
Granulocyte colony-stimulating factor
can be used for neutropenia,Stem
cell transplantation has been
successful in a few cases,
Medical Genetics
D,DiGEORGE anomaly
Thymic Hypoplasia
Third Pharyngeal Pouch Syndrome
Fourth Pharyngeal Pouch Syndrome
Medical Genetics
A congenital immunodeficiency
characterized pathologically by
absence or hypoplasia of the thymus
and parathyroid glands and
immunologically by partial or
complete T-cell immunodeficiency
but normal or near-normal B-cell
immunity,
Medical Genetics
Affected infants have low-set
ears,midline facial clefts,a small
receding mandible,hypertelorism,a
shortened philtrum,and congenital
heart disease,Tetany appears within
24 to 48 h of life,Both sexes are
equally affected,and familial cases
are uncommon,
Medical Genetics
Abnormalities of chromosome
22q (eg,deletion or monosomy) can
be identified in 90% of cases,There
seems to be an interruption of
normal development of pharyngeal
pouch structures near the 8th wk of
gestation,
Medical Genetics
Treatment
Bone marrow transplantation has
been successful,Some success has
been achieved with fetal thymus
transplants,The severity of the heart
disease often determines the
eventual prognosis,Partial deficiency
is compatible with prolonged survival,
Medical Genetics
E,Combined immunodeficiency
A group of disorders characterized
by congenital and usually hereditary
deficiency of both B- and T-cell
systems,lymphoid aplasia,and
thymic dysplasia,
Medical Genetics
Medical Genetics
Medical Genetics
The combined immunodeficiencies
include severe combined
immunodeficiency,Swiss
agammaglobulinemia,combined
immunodeficiency with adenosine
deaminase or nucleoside
phosphorylase deficiency,and
combined immunodeficiency with
immunoglobulins (Nezelof syndrome),
Medical Genetics
Most patients have an early
onset (within 3 mo of life) of
infection with thrush,pneumonia,
and diarrhea,If left untreated,most
die before age 2,Most patients have
profound deficiency of B cells and Igs,
Medical Genetics
The following are characteristic,
lymphopenia,low or absent T-cell
levels,poor proliferative response to
mitogens,cutaneous anergy,an
absent thymic shadow,and
diminished lymphoid tissue,
Pneumocystis pneumonia and other
opportunistic infections are common,
Medical Genetics
About 1/2 of patients with an
autosomal recessive inheritance have
adenosine deaminase (ADA)
deficiency,a purine salvage
pathway enzyme that converts
adenosine and deoxyadenosine to
inosine and deoxyinosine,
respectively,
Medical Genetics
ADA deficiency results in
elevated quantities of
deoxyadenosine triphosphate (dATP),
which inhibits DNA synthesis,ADA-
deficient patients may be normal at
birth but develop progressive
immunologic impairment as dATP
accumulates,
Medical Genetics
Treatment
Treatment with IG and antibiotics is
indicated but not curative,Treatment of
choice for all variants is stem cell
transplantation,Patients with ADA
deficiency have been treated successfully
with polyethylene glycol conjugated to
bovine ADA (PEG-ADA),IL-2-deficient
patients have been treated with
recombinant human IL-2,Gene therapy
has been used with some success in ADA
deficiency,
