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Clinical Immunology & SerologyA 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

Immunodeficiency DiseasesFigure 16-1



Immunodeficiency Diseases 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases – BA 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.



Immunodeficiency Diseases – BA 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.



Immunodeficiency Diseases – BA 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases 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.



Immunodeficiency Diseases – CGD 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.



Immunodeficiency Diseases – CGD 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.



Immunodeficiency Diseases 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.



Immunodeficiency Disease 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.



Immunodeficiency Disease 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.



Immunodeficiency Disease 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.



Immunodeficiency Disease 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.



Immunodeficiency Disease 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.



Immunodeficiency Disease 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.



Immunodeficiency Disease 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.



Immunodeficiency Disease 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).



Immunodeficiency Disease 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).



Immunodeficiency Disease 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.



Immunodeficiency DiseaseFigure 16-2



Immunodeficiency Disease 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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recurrent bacterial

severe recurrent infections

viral infections

normal adult levels

iga levels

t cells

immune system

pyogenic bacterial infections