Ch16 (3)

Clinical Immunology & Serology
A Laboratory Perspective, Third Edition
Copyright © 2010 F.A. Davis CompanyCopyright © 2010 F.A. Davis Company
Immunodeficiency Diseases
Chapter Sixteen

Copyright © 2010 F.A. Davis Company
Figure 16-1

 Because the components of the humoral and
cell-mediated portions of the immune system
interact extensively through many regulatory
and effector loops, a defect in one arm of the
system may affect other aspects of immune
function as well.
 With the exception of IgA deficiency,
primary immunodeficiency syndromes are
rare.

 A deficiency of one component of the system is
often accompanied by hyperactivity of other
component, including allergic or autoimmune
manifestations.
 More than 120 different congenital forms of
immunodeficiency have been reported, including
defects in lymphoid cells, phagocytic cells, and
complement proteins. Some are X-linked; some
are autosomal recessive. When NK cells are
reduced, there is a higher rate of malignancy.

 The clinical symptoms associated with immune
deficiencies range from very mild or subclinical to
severe recurrent infections or failure to thrive.
 In general, defects in humoral immunity result in
pyogenic bacterial infections, particularly of the
upper and lower respiratory tract.
 Complement deficiencies result in recurrent
bacterial infections and autoimmune problems.

 Defects in T-cell-mediated immunity result in
recurrent infections with intracellular
pathogens such as viruses, fungi, and
intracellular bacteria.
 These patients are also prone to
disseminated viral infections, especially with
latent viruses such as herpes simplex,
varicella zoster, and cytomegalovirus.

 The mechanisms of the agammaglobulinemias
include genetic defects in B-cell maturation or
mutations leading to defective interactions
between B and T cells.
 Only the more common and well-characterized
syndromes are described here and are
summarized in Table 16-1.

 In evaluating immunoglobulin deficiency
states, it is important to remember that blood
levels of immunoglobulins change with
age.
 IgM reaches normal adult levels first, around 1
year of age, followed by IgG at about 5 to 6
years of age.
 In some normal children, IgA levels do not
reach normal adult values until adolescence.

Immunodeficiency Diseases – THI
 All infants experience low levels of
immunoglobulins at approximately 5 to 6
months of age, but in some cases, the low
levels persist for a longer time.
 Transient hypogammaglobulinemia of
infancy may result.
 The mechanism of this transient
hypogammaglobulinemia is not known.

Immunodeficiency Diseases – BA
 Bruton’s agammaglobulinemia, first
described in 1952, is X chromosome–linked,
and so affects males almost exclusively.
 Patients with X-linked agammaglobulinemia
lack circulating mature CD19 positive B cells
and exhibit a deficiency or lack of
immunoglobulins of all classes.

 Patients have no plasma cells in their
lymphoid tissues, but they do have pre-B cells
in their bone marrow.
 T cells are normal in number and function.
 These patients develop recurrent bacterial
infections beginning in infancy, as maternal
antibody is cleared.

 X-linked hypogammaglobulinemia results from
arrested differentiation at the pre-B cell stage,
leading to a complete absence of mature B
cells and plasma cells.
 The underlying genetic mechanism is a
deficiency of an enzyme called the Bruton
tyrosine kinase (Btk) in B-cell progenitor cells.

 Lack of the Btk enzyme apparently causes a
failure of Vh gene rearrangement.
 The syndrome can be differentiated from
transient hypogammaglobulinemia of infancy
by the absence of CD19 positive B cells in the
peripheral blood, by the abnormal histology of
lymphoid tissues, and by its persistence
beyond 2 years of age.

Immunodeficiency Diseases – IgA Def
 Most patients with IgA deficiency are
asymptomatic. This is the most common
congenital immune deficiency and appears to
be a failure in isotype switching in B cells.
 Those patients with symptoms usually have
infections of the respiratory and
gastrointestinal tract and an increased
tendency to autoimmune diseases and
allergies

Immunodeficiency Diseases – CVI
 Common variable immunodeficiency (CVI)
is a heterogeneous group of disorders ,
leading to IgG and IgA deficiencies
 The disorder can be congenital or acquired,
familial or sporadic, and it occurs with equal
frequency in men and women.
 leads to recurrent bacterial infections,
particularly sinusitis and pneumonia.

Immunodeficiency Diseases – CVI
 In contrast to X-linked agammaglobulinemia,
most patients with CVI have normal numbers
of mature B cells, but they fail to transform into
plasma cells.

 Defects in cell-mediated immunity can
result from abnormalities at many different
stages of T-cell development.
 In some cases, a primary defect in cell-
mediated immunity can also have secondary
effects on humoral immunity.

Immunodeficiency Diseases – DGA
 The immunodeficiency associated with the
DiGeorge anomaly is a quantitative defect in
thymocytes due to a developmental defect in
the thymus.
 Insufficient mature T cells are made, but those
that are present are functionally normal. May
undergo bone marrow or thymus transplant.

 Defects in both humoral (B cell) and cell-
mediated (T cell) immunity can be caused
by a defect that affects development of both
types of lymphocytes or a defective interaction
between the two limbs of the immune system.

Immunodeficiency Diseases – SCID
 The most serious of the congenital immune
deficiencies is severe combined
immunodeficiency (SCID).
 SCID is actually a group of related diseases
that all affect T- and B-cell function but with
differing causes.
 X-linked SCID is the most common form of the
disease, presenting in early infancy with
multiple types of infections.

Immunodeficiency Diseases – SCID
 The abnormal gene involved codes for a
protein chain called the common gamma
chain, which is common to receptors for
interleukins 2, 4, 7, 9, 15, and 21.
 The gene is referred to as the IL2RG gene
and is located on the X chromosome.
 Normal signaling cannot occur in cells with
defective receptors, thus halting proliferation
and maturation.

 Chronic granulomatous disease (CGD) is a
group of disorders inherited as either an X-
linked or autosomal recessive gene that
affects neutrophil microbicidal function.
 X-linked disease accounts for 70 percent of
the cases, and it tends to be more severe.
 CGD is the most common and best
characterized of the neutrophil
abnormalities.

Immunodeficiency Diseases – CGD
 There are three different autosomal recessive
genes involved, and all of these affect subunits
of nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase.
 Normally, neutrophil stimulation leads to the
production of reactive oxygen molecules, such
as hydrogen peroxide (H2O2), by NADPH
oxidase on the plasma membrane.

 Neutrophil granules fuse with, and release
their contents into, the forming phagosome, as
organisms are phagocytized.
 Hydrogen peroxide is then used by the granule
enzyme myeloperoxidase to generate the
potent microbicidal agent hypochlorous acid.
 In CGD, neutrophils are unable to undergo the
oxidative burst.

 CGD was historically diagnosed by measuring
the ability of a patient’s neutrophils to reduce
the dye nitro-blue tetrazolium (NBT).
 More recently, a flow cytometric assay has
become available.
 Patients have a deficiency in G6PD for
hydrogen peroxide production, or
myeloperoxidase activity for hypochlorite
production

Immunodeficiency Diseases – NGDD
 Even if microbicidal activity is normal,
neutrophils cannot perform their functions
properly if they fail to leave the vasculature
and migrate to a site of incipient infection.
 Adhesion receptors on leukocytes (integrins)
and their counter-receptors on endothelial
cells (selectins) and extracellular matrix play
important roles in these activities.

 In leukocyte adhesion deficiency (LAD), a
protein (CD18) that is a component of
adhesion receptors on neutrophils and
monocytes (with CD11b or CD11c) and on T
cells (with CD11a) is defective.
 This defect leads to abnormal adhesion,
motility, aggregation, chemotaxis, and
endocytosis by the affected leukocytes.

Immunodeficiency Diseases – LAD
 The defects are clinically manifested as
delayed wound healing, chronic skin
infections, intestinal and respiratory tract
infections, and periodontitis.
 A defect in CD18 can be diagnosed by
detecting a decreased amount of the CD11/18
antigen on patient leukocytes by flow
cytometry.

Immunodeficiency Disease
 Deficiencies in each of the major
complement components have been
described, leading to various clinical
sequelae.
 Deficiencies in the early complement
components, C1q, 4, and 2, are usually
associated with a lupus-like syndrome.
 Deficiency of C2 is believed to be the most
common complement component deficiency.

 A C3 deficiency may also have a lupus-like
clinical presentation but is more likely to
involve recurrent encapsulated organism
infection.
 Deficiencies of the later components of
complement (C5–C9) are often associated
with recurrent Neisseria meningitidis
infections.

 Screening tests used for the initial
evaluation of suspected immunodeficiency
states are summarized in Table 16-3.
 Measurement of the levels of serum IgG, IgM,
and IgA and levels of the subclasses of IgG
are used to screen for defects in antibody
production.

 An overall assessment of antibody-mediated
immunity can be made by measuring antibody
responses to antigens to which the population
is exposed normally or following vaccination.
 Delayed-hypersensitivity-type skin reactions
can be used to screen for defects in cell-
mediated immunity.

 Screening for complement deficiencies
usually begins with a CH50 assay to
determine the level of functional complement
in an individual.
 See Chapter 6 for details of the CH50 assay.
 Defects in neutrophil oxidative burst
activity may be detected by a flow cytometric
assay, as mentioned earlier.

 If the screening tests detect an abnormality
or if the clinical suspicion is high, more
specialized testing will probably be
necessary to precisely identify an immune
abnormality.
 Some of the tests used for confirming an
immunodeficiency state are summarized in
Table 16-4.

 Enumeration of classes of lymphocytes in the
peripheral blood, bone marrow, and lymph
nodes is performed by flow cytometry.
 For example, an absence or profound
decrease in the number of CD3 positive cells
would be consistent with DiGeorge syndrome.
 An absence of CD19 positive B cells suggests
Bruton’s agammaglobulinemia.

 Genetic testing is available for many
conditions, including the DiGeorge deletion,
the Wiskott-Aldrich gene, and the IL2RG
mutations in SCID.
 T-cell function can be measured by
assessing the ability of isolated T cells to
proliferate in response to an antigenic stimulus
or to nonspecific mitogens in culture.

 Quantitative measurement of serum or
urine immunoglobulins by protein
electrophoresis is used in the workup of both
immunodeficiency states and some
lymphoproliferative disorders.
 Protein electrophoresis allows reproducible
separation of the major plasma proteins (see
Chapter 4 for details).

 Additional evaluation of serum immunoglobulin
is performed if the SPE shows a monoclonal
component or if there is a significant
quantitative abnormality of serum
immunoglobulins.
 Another method of characterizing immune
deficiencies is immunofixation
electrophoresis (IFE).

 Polyclonal immunoglobulins are indicated by
areas of diffuse staining, while monoclonal
bands produce narrow, intensely stained
bands.
 Lack of bands indicates immunodeficiencies of
one or more immunoglobulin classes.
 Refer to Figure 15-2 in Chapter 15 for
details regarding immunofixation.
 See Figure 16-2 for further examples of IF.

Figure 16-2

 Specific immunoglobulin isotype levels
can be determined by nephelometry.
 A bone marrow aspirate and biopsy is
indicated in any evaluation of monoclonal
gammopathy or immunodeficiency state.

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