Primary immunodeficiencies, rare disorders with genetic origins,

are seen primarily in infants and young children. To date, more

than 95 immunodeficiencies of genetic origin have been identified
(Buckley, 2000). Symptoms usually develop early in life after
protection from maternal antibodies decreases. Without treatment,
infants and children with these disorders seldom survive to
adulthood. These disorders may involve one or more components
of the immune system. Symptoms of immune deficiency diseases
are related to the role that the deficient
component normally
plays

PHAGOCYTIC DYSFUNCTION
Pathophysiology
A variety of primary defects of phagocytes may occur; nearly all of
them are genetic in origin and affect the innate immune system.
In some types of phagocytic disorders, the neutrophils are impaired
so that they cannot exit the circulation and travel to sites of
infection. As a result the patient cannot mount a normal inflammatory
response against pathogenic organisms (Lekstrom-Himes
& Gallin, 2002). In some disorders, the neutrophil count may be
very low; in others, it may be very high because the neutrophils remain
in the vascular system.

B-CELL DEFICIENCIES
Pathophysiology
Two types of inherited B-cell deficiencies exist. The first type results
from lack of differentiation of B-cell precursors into mature
B cells. As a result, plasma cells are lacking, and the germinal
centers from all lymphatic tissues disappear, leading to a complete
lack of antibody production against invading bacteria,
viruses, and other pathogens. Infants born with this disorder suffer
from severe infections starting soon after birth. This syndrome
is called sex-linked agammaglobulinemia (Brutons disease) because
all antibodies disappear from the patients plasma. B cells
in the peripheral blood and the immunoglobulins IgG, IgM, IgA,
IgD, and IgE are low or absent. The prevalence of this disorder is
approximately 1 case per 100,000 population (Parslow, Stites,
Terr & Imboden, 2001).
The second type of B-cell deficiency results from a lack of
differentiation of B cells into plasma cells. Only diminished antibody
production occurs with this disorder. Although plasma
cells are the most vigorous producers of antibodies, affected patients
have normal lymph follicles and many B lymphocytes
that produce some antibodies. This syndrome, called hypogammaglobulinemia,
is a frequently occurring immunodeficiency.
It is also called common variable immunodeficiency
(CVID), a term that encompasses a variety of defects ranging
from immunoglobulin A (IgA) deficiency, in which only the
plasma cells that produce IgA are lacking, to the other extreme,
in which there is severe panhypoglobulinemia (general lack of
immunoglobulins in the blood).
CVID is the most common primary immunodeficiency seen
in adults; it can occur in either gender. Although it can occur at
any age, its onset is most often in the second decade of life. The
vast majority of patients do not become symptomatic until 15
to 35 years of age. The major immunologic features of CVID include
recurrent pyogenic infections, an increased incidence of
autoimmune diseases, and a decreased level of total immunoglobulins,
with IgG below 250 mg/dL. The B-cell numbers usually
remain normal. The etiology of this disorder is unknown and 1 case per 80,000 population in the United
States (Tierney,
McPhee & Papdakis, 2001).

T-CELL DEFICIENCIES
Pathophysiology
Defects in T cells lead to opportunistic infections. Most primary
T-cell immunodeficiencies are genetic in origin. An increased susceptibility
to infection is common. Symptoms can vary considerably
depending on the type of T-cell defect. Because the T cells
play a regulatory role in immune system function, the loss of T-cell
function is usually accompanied by some loss of B-cell activity.
DiGeorge syndrome, or thymic hypoplasia, is one example
of a primary T-cell immunodeficiency. This rare congenital disease
results from the absence of several genes on chromosome 22
(Porth, 2002). The variation in symptoms is a result of differences
in the amount of genetic material affected. T-cell deficiency occurs
when the thymus gland fails to develop normally during embryogenesis.
DiGeorge syndrome is one of the few immunodeficiency
disorders with symptoms that present almost immediately following
birth (Parslow et al., 2001).
Chronic mucocutaneous candidiasis with or without endocrinopathy
is another T-cell disorder associated with a selective
defect in T-cell immunity; it is thought to be caused by an autosomal
recessive inheritance, affecting both males and females. It
is considered an autoimmune disorder in which the thymus and
other endocrine glands are involved in the autoimmune process.
The disease causes extensive morbidity resulting from endocrine dysfunction.

COMBINED B-CELL
AND T-CELL DEFICIENCIES

Pathophysiology
Combined B-cell and T-cell deficiencies are those disorders of
the immune system that have elements of dysfunction of both the
B cells and T cells. A variety of inherited (autosomal recessive and
X-linked) conditions fit this description. These conditions have
in common disruption of the normal communication system of
B cells and T cells and impairment of the immune response
(Porth, 2002). These conditions generally appear early in life. Examples
of these deficiencies are discussed below.
Ataxia-telangiectasia is an autosomal recessive disorder affecting
both T- and B-cell immunity. In 40% of patients with
this disease, a selective IgA deficiency exists. IgA and IgG subclass
deficiencies, along with IgE deficiencies, have been identified.
Variable degrees of T-cell deficiencies are observed and become
more severe with advancing age. The disease is associated with
neurologic, vascular, endocrine, hepatic, and cutaneous abnormalities.
It is accompanied by progressive cerebellar ataxia, telangiectasias,
recurrent bacterial infection of the sinuses and lungs, and
an increased incidence of cancer (Buckley, 2000).
Both B and T cells are missing in severe combined immunodeficiency
disease (SCID). SCID is a phenotypic term that is
used for a wide variety of congenital and hereditary immunologic
defects that are characterized by early onset of infections, defects
in both B- and T-cell systems, lymphoid aplasia, and thymic dysplasia.
Inheritance of this disorder can be X-linked, autosomalrecessive,
or sporadic. The exact incidence of SCID is unknown;
it is recognized as a rare disease in most population groups, with
an incidence of about 1 case in 1,000,000. This illness occurs
in all racial groups and both genders (Parslow et al., 2001).
Wiskott-Aldrich syndrome is a variation of SCID compounded by thrombocytopenia (loss of platelets).
The prognosis is generally
poor because most affected infants develop overwhelming
fatal infections

COMPLEMENT SYSTEM
The complement system is an integral part of the immune system,
and alterations in normal components of complement can result
in increased susceptibility to infectious diseases and to immunemediated
disorders (Porth, 2002). Improved techniques to identify
the individual components of the complement system have led
to a steady increase in the number of deficiencies identified. Disorders
of the complement system can be primary or secondary. C2 and C3 component deficiencies result in
diminished resistance
to bacterial infections. Angioneurotic edema is caused by
an inherited deficiency of the inhibitor of C1 esterase, which opposes
the release of inflammatory mediators. A deficiency of this
inhibitor results in frequent episodes of urticaria and edema in
various parts of the body.
Patients with paroxysmal nocturnal hemoglobinuria (PNH)
lack decay-accelerating factor (DAF), which is found on erythrocytes
(red blood cells). DAF normally protects the erythrocytes
from lysis (disintegration). In PNH, the complement component
C3b accumulates on the CR1 molecule on the erythrocyte, acts
as a binding site for the late-acting component, and allows lysis
to occur.