358
U N I T 4
Infection and Immunity
Immunodeficiency Disorders
Immunodeficiency can be defined as an abnormality in
one or more components of the immune system that
renders a person susceptible to diseases normally pre-
vented by an intact immune system. These disorders
can be broadly classified into two groups: primary
and secondary.
1
The primary or congenital immuno-
deficiencies are genetic defects that result in increased
susceptibility to infection that is frequently manifested
early in life. Secondary or acquired immunodeficiency
is not inherited but develops as a consequence of mal-
nutrition, selective loss of immunoglobulins through
the gastrointestinal or genitourinary tracts, treatment
with immunosuppressant drugs, or human immuno-
deficiency virus (HIV), the etiologic agent of acquired
immunodeficiency syndrome (AIDS). Regardless of the
cause, primary and secondary deficiencies can produce
the same spectrum of disease. The severity and symp-
tomatology of the various disorders depend on the type
and extent of the deficiency.
Primary Immunodeficiency
Disorders
Until recently, little was known about the causes of
primary immunodeficiency diseases. However, this
has changed with recent advances in genetic technol-
ogy.
1,32–35
To date, more than 180 primary immunode-
ficiency syndromes have been identified, and specific
molecular defects have been identified in more than
one third of these diseases.
1
Most are transmitted as
recessive traits, caused by mutations in genes on the
X chromosome or autosomal chromosomes. Many of
these disorders have been traced to mutations affect-
ing signaling pathways (e.g., cytokines and cytokine
signaling, receptor subunits, and metabolic pathways)
that dictate immune cell development and function.
Furthermore, it has been shown that the immune sys-
tem is a carefully balanced system that is designed to
distinguish between self and nonself; therefore, symp-
toms of autoimmunity often are observed with primary
immunodeficiency disease.
Early detection, which is possible for most pri-
mary immunodeficiency diseases, is critical for the
success of some treatments and can be lifesaving. For
infants with severe combined T- and B-cell immuno-
deficiency, early diagnosis is essential in terms of not
only preventing life-threatening infections, but also
preventing administration of live attenuated virus
vaccines (e.g., measles, mumps, rubella, varicella),
which could prove fatal.
35
The first clinical clue for
the diagnosis of a primary immunodeficiency disease
is usually a history of infections that are persistent,
difficult to treat, or caused by unusual microbes.
The Jeffrey Modell Foundation/Immune Deficiency
Foundation has developed a set of warning signs that
serve as an excellent tool for determining what should
be considered abnormal (Chart 16-2).
36
Because these
disorders are frequently inherited, a positive family
history is also a key diagnostic tool. The type of infec-
tion can provide information regarding the type of
defect that is present. Infections with bacterial organ-
isms are frequently observed in cases of antibody defi-
ciency, whereas severe viral, fungal, and opportunistic
infections characterize T-cell deficiencies. Recurrent
Streptococcus pneumoniae
or
Neisseria
infections
characterize persons with complement deficiencies,
and recurrent infections with staphylococcal and
other catalase-positive organisms indicate disorders
of phagocytosis.
Humoral (B-Cell) Immunodeficiency
Disorders
Of all the primary immunodeficiency diseases, those
affecting antibody production and humoral immunity
are the most common.
35
Antibody production depends
on the differentiation of hematopoietic stem cells into
mature B lymphocytes and the antigen-dependent gen-
eration of immunoglobulin-producing plasma cells
37,38
(Fig. 16-6). This maturation cycle initially involves
the production of surface IgM, migration from the
bone marrow to the peripheral lymphoid tissue, and
switching to the production of specialized IgM-, IgA-,
IgD-, IgE-, or IgG-secreting plasma cells after antigenic
stimulation. Primary humoral immunodeficiency disor-
ders can interrupt the production of one or all of the
immunoglobulins.
Defects in humoral immunity increase the risk
of recurrent pyogenic infections, including those
caused by
S. pneumoniae, Haemophilus influenzae,
Staphylococcus aureus,
and
Pseudomonas
species.
Humoral immunity usually is not as important in
defending against intracellular bacteria (mycobacteria),
fungi, and protozoa. Viruses usually are handled nor-
mally, except for the enteroviruses that cause gastroin-
testinal infections.
CHART 16-2
TenWarning Signs of Primary
Immunodeficiency
■■
Four or more new ear infections within 1 year
■■
Two or more serious sinus infections within 1 year
■■
Two or more months on antibiotics with little effect
■■
Two or more pneumonias within 1 year
■■
Failure of an infant to gain weight or grow normally
■■
Recurrent, deep skin or organ abscesses
■■
Persistent thrush in mouth or fungal infections of the
skin
■■
Need for intravenous antibiotics to clear infections
■■
Two or more deep-seated infections including
septicemia
■■
A family history of primary immunodeficiency
These warning signs were developed by the Jeffrey Modell
Foundation Medical Advisory Board. Consultation with
primary immunodeficiency experts is strongly suggested.
© Jeffrey Modell Foundation.
