Immunodeficiency

The human body is constantly bombarded by infectious microbes, including
bacteria, fungi, viruses, parasites, and countless others. These can cause
problems ranging from disease to even death and must be somehow kept under
control. For this reason, the body has a highly complex immune system, which
utilizes various responses in order to fight infection and infectious
microbes. This system though, is itself susceptible to defects.

It is these immunodeficiency disorders which can cripple the immune system
and hurt the body's ability to fight infection. The first of these diseases
was introduced in detail in 1952 by Ogdon Carr Bruton (X-linked
agammaglobulinemia) (Silverstien, 1989). Since then dozens of different
disorders have been diagnosed. These disorders can be divided into several
groups. There are antibody (B-cell) diseases, combined antibody (B-cell) and
cell-mediated (T- cell) diseases, phagocytic dysfunctions, and complement
abnormalities (Fundenberg, 1980).

Recurrent infection is the hallmark of an immunodeficient patient. There is
an increase in the incidence of infection in almost all of the
immunodeficient diseases. The nature of the deficit determines the spectrum
of infections that may be encountered, thus primary T cell deficiencies with
diminished cell- mediated immunity permit an unusual amount of intracellular
infections which may be caused by viruses fungi and certain bacteria (Thaler,
1977). B cell deficits allow infections by organisms that are largely
disposed by opsonization, that is, by encapsulated bacteria such as
pneumococcus and staphylococcus.

Ab Immunodeficiency Diseases

Hypogammaglobulinemia

X-Linked Hypogammaglobulinemia Symptoms

This was the very first immunodeficiency disease to be discovered. It was
discovered by Bruton in 1952 (Thaler, 1977). It was found mainly in young
males who where present with recurrent infections of pneumonia, otitis,
sinusitis, and meningitis beginning about the age of six months. The
passive transfer of immunoglobulin from fetal life affords protection from
the pathogens for the first 6 months of life.

These young patients primarily suffer from bacterial infections, especially
capsulate pneumococci and streptococci, where they are less susceptible to
viral and fungal infections, excluding the hepatitis virus. Some patients
have also been reported to display prolonged shedding of the polio virus
after vaccination (Thaler, 1977). Other complications from this
immunodeficiency, which occurs in about 50% of the patients is rheumatoid
arthritis, dermatomytosis and an increased incidence of lymphoreticular
malignancies (Thaler, 1977).

X-Linked Hypogammaglobulinemia Features

In the X-Linked Hypogammaglobulinemia, there is a very low number of
circulating immunoglobulin of all classes. Another symptom of this disease
is that the peripheral lymphoid tissue is hypoblastic and the lymph nodes
lack cortical follicles, germinal centers and plasma cells. In spite of
this, the peripheral blood lymphocyte levels are usually normal (Thaler,
1977).

These patients also have deficient humoral immunity and are unable to
opsonize bacteria for eventual phagocytosis and clearance from the body.
This humoral unresponsiveness against both the T Cell dependant and T Cell
independent antigens is strong evidence for a B Cell defect.

In most cases there is an absence of immunoglobulin bearing cells, but the
patient may have a normal number of cells bearing complement receptors. The
cellular immune system seems to be confident in handling viral, fungal,
parasitic and intracellular infections (Thaler, 1977). The thymus seems to
develop normally, and the thymic dependant area of the peripheral lymphoid
tissue is well populated with lymphocytes. Spontaneous rosette formation,
allograft rejection and the development of cutaneous hypersensitivity are all
normal and the only evidence of impairment is the in vitro response to
mitogens (Thaler, 1977).

Hypogammaglobulinemia Treatment

X-Linked Hypogammaglobulinemia Treatment

Patients have been treated with periodic injections of gammaglobulin, which
reduces the incidence of many infections. The only down side to this
treatment is the fact that sinopulmonary infections will often persist since
secretory IgA cannot be replaced by injections of immunoglobulin (Thaler,
1977).

Transient Hypogammaglobulinemia

Infants are initially protected by their mother's IgG. Through the first four
to five months of their life there is a decrease in this IgG and an increase
in IgA and IgM until at five to six weeks the IgG concentration in the blood
is at its lowest. At this point it is quite common for many infants to
undergo a period of temporary hypogammaglobulinemia characterized by
recurrent pulmonary infections. In the normal situation the infant will
begin to synthesize its own IgG but in transient hypogammaglobulinemia this
process can be retarded. This retardation can be present for two to three
years, leaving the child susceptible to pyogenic infection (Fundenberg,
1980).

Transient Hypo: Treatments

The cause of this disorder is unknown and if severe enough it can be treated
with the techniques used in treating X-linked Hypogammaglobulinemia (Gamma
globulin therapy for the duration of their deficiency) (Fundenberg, 1980).

CVID

Common Variable Immmunodeficiency is a variation on hypogammaglobulinemia.
In this case the affected individual develops the problems usually between
the ages of 10 and 20 years as in X-Linked hypogammaglobulinemia. Most
patients have B-cells present in the blood or lymph nodes that do not
function properly. Only small amounts of IgG are present and the body has no
IgA, IgM, IgE or IgD (Fundenberg, 1980).

Common variable immunodeficiency patients are unusually susceptible to
intestinal protozoa pyogenic organisms, and also have a high incidence of
autoimmune disease. Autoimmune diseases are those which cause the immune
system to treat "self" components of the body as foreign (Fundenberg, 1980).

The cause of this disease is unknown, although the symptoms seem to be a
result of the decreased synthesis or decreased release of immunoglobulins by
faulty B cells (Fundenberg, 1980).

Treatment of common variable immunodeficiency is identical to that of
X-Linked hypogammaglobulinemia. Gamma-globulin, fresh frozen plasma and
continuous antibodies are administered in order to alleviate the disease
while the symptoms (pyogenic infection, protozoa, autoimmune disorders) must
also be treated (Fundenberg, 1980).

Hyper-IgM Syndrome

Hyper-IgM syndrome is believed to have an X-linked mode of inheritance but
recent occurrences in females place this belief in some doubt. Children are
mainly affected and suffer from similar infections similar to those
encountered by children with X-linked hypogammaglobulinemia with a marked
susceptibility to pyogenic bacteria (Thaler, 1977). Infections are most
commonly found in the respiratory tract and the patients are usually present
with generalized lymphadenopathy, enlarged tonsils, adenoids and splenomegaly
(Freedman, 1976).

The diagnosis for hyper-IgM syndrome is established in the laboratory, by the
assay immunoelectrophoresis. The results reveals a marked diminution of IgA
and IgG with normal or more commonly, elevated levels of IgM. The IgM does
not form a monoclonal spike but is a rather broad , polyclonal band (Thaler,
1977).

The lymph nodes of the patient appear normal but patients may have diminished
numbers of follicular plasma cells, normal circulating lymphocytes, and some
patients can produce at least some antigen specific IgM (Freedman, 1976).

Most of the patients have lost the usual negative feedback that IgG may exert
upon 19s IgM production, and an intrinsic defect in B cell population may
prevent the switch from IgM to IgG, resulting in excess IgM production
(Thaler, 1977).

Some examples suggest that the addition of exogenous IgG will lower the IgM
level in the patients. These patients may also lack appropriate T Cell
helper function, of which IgG is heavily depended upon, which may result in
the response to only T- independent antigens (Thaler, 1977).

Selective IgA Deficiency

Selective IgA deficiency is the most common of all of the immunodeficiency
disorders, affecting one in every five hundred people. There is a strong
familial tendency and because of this the deficiency appears to inherited,
but the mode of inheritance is not known. Although autosomal recessive and
autosomal dominant with variable penetrance are considered to be most likely
modes of transmission (Thaler, 1977).

These patients have almost a complete absence of both serum and secretory
IgA. These patients also appear to be asymptomatic. There is increasing
evidence that the deficiency is frequently associated with a definite symptom
complex:

1. Most common symptoms are referable to the mucosal surfaces, most report
recurrent sinopulmonary infections, gastrointestinal manifestations can
include gluten-sensitive enteropathy, ulcerative colitis , pernicious anemia
and intestinal disaccharide deficiency. Malabsorption is a relatively
frequent problem and is often caused by chronic infection with Giardia.

2. Some atopic disease is present in about 50% of symptomatic patients,

3. Individuals with selective IgA deficiency have an increased amount of
autoimmune phenomena and autoimmune disease including haemolytic anemia,
Addison's disease , SLE, rheumatoid arthritis, and others. Various
auto-antibodies can be demonstrated including anti- IgA [50%], anti-IgM [35%]
and anti-collagen [35%]. These auto-antibodies may exist in the absence of
any overt clinical manifestations

4. These individuals have a high incidence of malignancies compared to normal
controls, including malignancies of the lung, gastrointestinal tract and
lymphoreticular system (Thaler, 1977).

Patients lack IgA, both serum and secretory. The function of secretory IgA
is not quite understood but secretory IgA has a well defined role as the
major class of immunoglobulin present in secretions. Secretory IgA may
contribute to the neutralization of infectious agents at their portal of
entry and has been postulated to limit the absorption of antigens from the
outside, including ones breathed and eaten.

Secretory IgA has also been postulated to prevent the reabsorption of certain
self antigens, such as those present on mucosal surfaces that are continually
being shed into the bodies secretions (Thaler, 1977). With a deficiency in
secretory IgA, the body could become flooded with common and uncommon
antigens. This process known as antigen flooding could account for the
following:

1. Atopy: antigens normally excluded by IgA could react with IgE bound to
mast cells and produce immediate hypersensitivity.

2. Autoimmune Disease: increase the systemic immune system encountering
antigens which cross-react with self determinants and elicit auto-antibody
structure.

3. Malignancy: Chronic irritations or inflammation resulting from a high
antigenic load could be responsible for the high incidence of pulmonary and
gastrointestinal cancers. IgA deficiency could result form lack of precursor
IgA secreting cells, many investigators feel that IgA secreting cells express
Iga on their surface.

It has been hypothesized that the IgA committed B cells are incapable of
differentiating into IgA producing plasma cells. Also, IgA production has
strict requirement for T cell Helper function and is perhaps most dependant
of all the immunoglobulin classes on T Cell Helper activity. In almost all
patients there is no evidence of T cell abnormality, although a diminished
amount of spontaneous rosette producing cells has be reported (Thaler, 1977).
IgA productions might be under the regulation of a suppressor mechanism. One
possibility is the presence of overactive IgA specific suppressor cells.

Most patients have detectable anti-IgA antibodies in their serum and are
usually IgA in nature and are directed against class specific heavy chain
determinants. The cell surface IgA may be a target for these auto-antibodies.
In some animal systems anti-alpha chain molecules have been found to prevent
the secretion of IgA, possibly binding to lymphocytes bearing surface IgA
(Thaler, 1977).

Selective IgM Deficiency

Selective IgM deficiency is a rare disorder associated with the absence of
IgM and normal levels of other immunoglobulin classes. Some patients are
capable of normal antibody responses in the other immunoglobulin classes
following specific immunization, whereas others respond poorly (Fundenberg,
1980). Cell mediated immunity seems to be intact. The cause of this disorder
is not well known. The absence of IgM with the presence of IgG appears to
contradict the theory of sequential immunoglobulin development.

Patients, both male and female, are susceptible to autoimmune disease and to
overwhelming infection with polysaccharide containing organisms. It would
appear to be logic to treat these patients with immediate antibiotic
(penicillin or ampicillin) treatment of all infections or with continuous
antibiotic treatment (Fundenberg, 1980).

T Cell Immunodeficiency Diseases

DiGeorge's Syndrome

This disorder is also known as congenital thymic hypoplasia. It presents the
neonate with hypocalcemic tetany due to severe hypoparathyrodism. Associated
malformations include tracheal , esophageal and cardiovascular anomalies
(notably a right sided aortic arch) and a characteristic facies with
hypertelorism, bowed mouth and notched pinnae.

Extensive mucocutaneous candidiasis is often present and is refractory to
normal antimycotic therapy. Most infections are usually fungal or viral in
nature, although gram negative bacteria infections are also seen (Thaler,
1977).

The underlying abnormalities is the dysmorphogenesis of the embryonic third
and fourth pharyngeal pouches, failure of the development of the thymus and
the parathyroid glands, with causes unknown. Thymus insufficiency is
responsible for the immunologic abnormalities in these children (Thaler,
1977).

Lymph node biopsy characteristically reveals marked diminution of the number
of lymphocytes in the paracortical regions [T Cell regions] (Fundenberg,
1980). The level of blood lymphocytes is usually normal, although some
children develop lymphopenia.

Surface characterization of peripheral lymphocytes reveals an abnormally high
percentage of cells bearing surface immunoglobulin and low numbers forming
spontaneous sheep erythrocyte rosettes. The ability to carry out T Cell
related functions is markedly impaired although it varies from patient to
patient.

T Helper Cell function may also be affected, though serum immunoglobulin
amounts are normal, the capacity to mount humoral responses to specific
antigens can be depressed.

The lost function of the thymus seems to result in the inability to produce a
normal population of thymus precursor lymphocytes, perhaps 10-20% of normal
amount (Thaler, 1977).

The most promising form of treatment is the transplant of human allogenic
fetal thymuses. Successful transplant reverses the immunodeficiency state
and the development of mature and functioning T cells occurs. This does
occur because the donor thymus is fetal, and it is generally believed that
lymphocytes carried in the graft cannot mount a graft-versus- host reaction
(GVH) against the recipient, thus the new thymus is not rejected and
recognized as self (Thaler, 1977).

CMC

Chronic Mucocutaneous Candidiasis (CMC) affects both males and females, and
is noted to be autosomal recessive. It is associated with a selective defect
in cell mediated immunity, resulting in chronic candidal infection
(Fundenberg, 1980). Antibody mediated immunity is intact, resulting in
normal antibody response to Candida. This disorder may appear as early as 1
year of age or may be delayed until the second decade.

The initial presentation may be either chronic candidal infection of mucous
membranes, nails and skin or the appearance of an idiopathic endocrinopathy.
In severe forms, infection is associated with the formation of granulomatous
lesions. Studies reveal a specific though variable defect in T cell
immunity. Patients usually have normal total lymphocyte count.

Plasma inhibitors of T Cells function and increased numbers of suppressor T
cells have been reported. Other abnormalities include hypoparathyroidism
which is associated with decreased serum calcium, elevated serum phosphorus
and low or absent parathyroid hormone (Fundenberg, 1980).

Increased skin pigmentation may herald the onset of Addison's disease prior
to disturbances in serum electrolytes. Other abnormalities of endocrine
function include hypothyroidism, abnormal vitamin B12 absorption, and
diabetes mellitus (Fundenberg, 1980).

Chronic Skin and mucous membrane candidal infection is difficult to treat
Topical treatment with a variety of antifungal agents has been attempted but
has usually been unsuccessful. Patients may survive to the second or third
decade but usually experience extreme morbidity (Freedman, 1976). Individuals
with severe candidal infection of the mucous membranes and skin develop
serious physiological difficulties. In the end, Addison's disease is the
major cause of death and may develop suddenly with out symptoms (Fundenberg,
1980).

Hyper-IgE Syndrome

Patients are plagued with recurrent pyogenic infections with the formation of
cutaneous , pulmonary and joint abscesses, chronic dermatitis and growth
retardation. An IgE aberration was first suggested by the observation of
exaggerated immediate hypersensitivity reactions. The high level of IgE in
these patients is polyclonal and is associated with eosinophilia. Immediate
hypersensitivity can be elicited by many antigens, and in this the other
immunoglobulin classes circulate at normal levels (Thaler, 1977).

IgE levels may be normal controlled by T Suppressor cells and a deficiency of
suppressor cells may contribute to the pathogenesis of this syndrome. This
view is supported by other evidence of T Cell dysfunction in these patients.
There is poor delayed hypersensitivity reactivity and these children can not
be sensitized to produce a cell mediated response against the common skin
test antigen, DNCB (dinitrochlorobenzene) (Thaler, 1977). Patients
lymphocytes do not respond to antigenic stimuli in vivo.

These patients also have marked deficiencies in their ability to mount
humoral responses against antigenic challenges, although they have normal
blood type iosagglutins, reminiscent of those patients with hyper IgM
syndrome (Freedman, 1976).

The abnormal in vivo antibody responsiveness in these patients may be
indicative of defective T Helper Function. The many indications of T Cell
dysfunction in these patients enhance the possibility that a deficiency of T
Suppression of IgE responses may be at fault here (Thaler, 1977).

MHC-II Deficiency

This deficiency involves the failure of the expression of class II major
histocompatibility molecules that are located on antigen presenting cells
including B-cells and macrophages. Affected infants are deficient in their
number of CD4+ T-cells, and this in turn can cause a deficiency in antibody
production (Roitt, 1993). Those affected experience recurrent infections,
especially of the gastrointestinal tract. The cause of this deficiency is a
defect in a promoter protein, inhibiting proper translation of the class II
major histocompatibility antigen genes (Roitt, 1993).

Ab & Cell Mediated Diseases

SCID

Patients born with severe combined immunodeficiency disease are both
lymphocytopenic and granulocytopenic, meaning they suffer from a severe
immunodeficiency of both the humoral and cellular limbs of the immune system
(Thaler, 1977). It is one of the most severe of all the immunodeficiency
states. In all forms of the SCID, radiographic analysis often reveals the
absence of adenoidal and thymic shadows as well as evidence of pneumonia.

There is also a high frequency of associated bony abnormalities in X-ray
including cupping and flaring of anterior rib ends (Fundenberg, 1980).
Inheritance can be autosomal recessive or X-Linked recessive although
sporadic cases have also been reported. It has become possible to divide
severe SCID into two types:

1. SCID with out any known biochemical defect, and

2. SCID with a deficiency in the enzyme adenosine deaminase (ADA).

In both these forms , the patients present before six months of age with
failure to thrive, these infants get severe infections, notably mucocutaneous
candidiasis with other infections being caused by viruses fungi and
opportunistic pathogens such as Pneumocystis carinii (Fundenberg, 1980).
Chronic pneumonia as well as diarrhea with malabsorption [often on an
infectious basis] are common. These children often die at a very young age
(Thaler, 1977).

SCID Without ADA Deficiency

These patients are markedly lymphopenic and both the T and B Cell areas of
the peripheral lymphoid tissue are depleted of lymphocytes (Thaler, 1977).
Their immunologic function is depressed by all measures. The patients are
anergic and cannot be sensitized to cutaneously applied antigens. Their
lymphocytes will not respond to antigens, allogenic cells or mitogens. These
patients do not make specific antibodies, their thymuses are small and
embryonic, lacking evidence of cortico-medullary differentiation in Hassall's
corpuscles (Thaler, 1977).

Investigators have attributed certain aspects of this global immunodeficiency
to the grossly abnormal thymus, unlike DiGeorge's syndrome, however, these
patients cells do not respond in vitro to thymic extracts indicating that the
primary defect may instead lie with an unresponsive precursor population
(Fundenberg, 1980). Thus fetal thymic transplantations are only rarely
helpful, and further support of primary precursor cell defect is derived from
the several reports of successful used of bone marrow transplants (Freedman,
1976).

SCID With ADA Deficiency

Most of these patients exhibit an absence of all immune function, they have
small involuted thymuses but the epithelium is well differentiated and
Hassall's corpuscles are present, which is a sign of thymic maturity. There
is severe lymphopenia reflected in a marked deficiency of lymphocytes in the
peripheral blood, lymph nodes and spleen and there are few if any Peyer's
patches (Thaler, 1977).

Of the lymphocytes found, they demonstrate immunologic incompetence and carry
few B or T cell markers. The cells are incapable of responding to antigenic
or mitogenic stimuli, and in the most severely affected patients there is
little or no detectable circulating immunoglobulin (Fundenberg, 1980).

ADA catalyzes the conversion of adenosine to inosine and therefore can
contribute to the regulation of intracellular adenosine levels. ADA exists
in several tissue-specific isoenzymatic forms, but no case of ADA deficiency
has yet been reported with a selective deficiency of only one or several of
these isoenzymes (Thaler, 1977).

ADA deficiency is inherited as and autosomal recessive trait and can be
diagnosed by measuring the level of the enzyme in the patient's red blood
cells. Parents of affected children have half the level of ADA, nevertheless
they are clinically normal. There are two ways in which a deficiency of ADA
could theoretically compromise immunological functions:

1. ADA deficiency might lead to high intracellular levels of adenosine, and
it has been suggested that high levels of adenosine can be toxic to the cell
by inhibiting pyrimidine synthesis and thereby leading to pyrimidine
starvation.

2. It is conceivable that a build up of adenosine could lead to and increase
in the intracellular levels of cyclic AMP, a molecule shown to inhibit many
aspects of lymphocyte function. The conversion of adenosine to cyclic AMP in
the presence of adenosine accumulation is compatible with the kinematics of a
least some of the enzymes involved (Thaler, 1977).

SCID With & Without ADA: Treatments

Treating this immunodeficiency is very difficult. In an attempt to assess
whether a thymic transplantation would be of value, patients's cells have
been treated in vitro with thymic extracts in a manner similar to that used
in DiGeorge's syndrome. This treatment was without effect in SCID patients
(Fundenberg, 1980).

Histocompatible bone marrow transplants have been attempted with occasional
success in reconstituting the immune system and in one instance
transplantation of fetal liver was a benefit, it is not known whether success
depends on the establishment of a viable donor lymphocyte line from which can
perform the required immunologic functions, or whether one is merely
providing donor cells with sufficient ADA to detoxify and reduce adenosine
levels (Thaler, 1977).

Since adenosine is permeable across membranes, reduction in one cellular
compartment could conceivably affect the adenosine levels elsewhere. A
recent report indicates that transfusions or normal red cells possessing high
levels of ADA may correct the immunologic defects (Thaler, 1977).

Nezelof's Syndrome

This is a syndrome of thymic dysplasia often associated with near normal or
even elevated levels of circulating immunoglobulin. This syndrome affects
children from about 6 months of age presenting failure to thrive, recurrent
infections [predominantly fungal and viral] and chronic diarrhea. It appears
to be inherited as either and autosomal or X-linked recessive trait
(Fundenberg, 1980).

The thymus is hypoplastic and embryonal in character with the absence of
Hassall's corpuscles and no cortomedullary differentiation (Fundenberg,
1980). There is also associated lymphopenia and a deficiency of well
differentiated T cells. This T cell dysfunction is evident in a decreased in
vitro responsiveness to mitogen and a failure to exhibit cutaneous delayed
hypersensitivity (Freedman, 1976).

B cell function is also impaired, about 50% of patients, these children are
unable to mount specific antibody responses to an antigenic challenge. Most
patients have plasma cells in their lymph nodes , but the lymph node
architecture is abnormal, lacking follicles and germinal centres (Fundenberg,
1980).

About 50% of patients with some dysgammaglobulinemia are usually deficient of
IgA alone or a deficiency of both IgA and IgG. These classes are highly
susceptible to a loss of T helper function (Thaler, 1977).

The variable age of onset of symptoms and the reports of progressive loss of
immunologic function, including declining immunoglobulin levels, raise the
fact that this is a degenerative disease (Thaler, 1977).

Aggressive treatment of infection is necessary. Patients failing to show an
antibody response after immunization should receive monthly gammaglobulin
treatment. A continuous broad spectrum antibiotic may also be useful.
Postural drainage is important to prevent chronic lung disease. Thymus
transplantation has been reported to provide reconstitution of T Cell
immunity and partial reconstruction of B Cell immunity (Thaler, 1977).

Ataxia-Telangiectasia

This is a progressive disease that is inherited as an autosomal recessive
trait. Early manifestations include truncal ataxia that progress to involve
the extremities and oculocutaneous telangiectasias that may appear at any
time from the patients birth to several years of age. But by the time the
patients reach the age of 3 there is an increased incidence of sinopulmonary
infections (Thaler, 1977).

Other abnormalities include insulin resistance, ovarian and testicular
dysgenesis, hepatic abnormalities and pigmentary changes. These patients
often show early aging including grey hair and atrophy of the skin. Most
patients succumb at an early age to the effects of chronic infections and
most commonly to the pulmonary insufficiency. These patients may also exhibit
an increased incidence of the lymphoreticular malignancies (Freedman, 1976).

It has been found that there is cerebellar cortical atrophy and degeneration
with the lose of Purkinje's cells and extensive pulmonary changes compatible
to chronic lung infection. Pathologic abnormalities have been associated in
virtually every organ in the body and include nucleomegalic aneuploidy and
bizarre cytoplasmic changes, and some investigator feel that these resemble
viral lesions (Fundenberg, 1980). The organs of the immune system are
histologically abnormal. The thymus is small and embryonal in character, and
one third of the patients are lymphopenic (Thaler, 1977).

An examination of the lymph nodes reveals few lymphocytes in both the B and T
Cell areas.

70% of patients have low levels of serum IgA and diminished secretory IgA
levels accounting for their sinopulmonary infections. Some patients have
also been found to contain anti-IgA antibodies. Serum levels of IgG and IgM
are usually in the normal range. IgE levels are almost always diminished or
absent (Thaler, 1977).

The ability to produce a response to an antigenic stimuli is variable. The
response to viral antigens seems to be more severely compromised than the
response to bacterial antigens. These patients consistently display subnormal
antiviral antibody titres despite normal quantitative IgM and IgG serum
levels. Cellular immunity has become greatly impaired with the passage of
time as measured by in vitro assays of mitogenic and antigenic activation. In
vivo evidence includes delayed allograft rejection and the inability to mount
cutaneous delayed hypersensitivity reactions (Freedman, 1976).

Early treatment of recurrent sinopulmonary infections is essential to avoid
permanent complications. Some patients may benefit from continuous broad
spectrum antibiotic therapy. Fetal thymus transplantation has provided some
benefit in a limited number of patients. One last suggestion is the monthly
injection of frozen plasma as a source of passively administered antibody
(Thaler, 1977).

Wiskott-Aldrich Syndrome

Wiskott-Aldrich Syndrome is an immunologic deficiency characterized by
thrombocytopenia, eczema, and recurrent infections. Thrombocytopenia is a
condition in which platelets are at a lower than normal concentration in the
body and eczema causes blistery skin rashes. The disease causes a decrease
in serum IgM and elevated serum IgA and IgE (Roitt, 1993).

T-cells are also defective, more so throughout life, and have an abnormal
appearance. At birth, thrombocytopenia is already present, the platelets also
being small and abnormally shaped. At 6 months recurrent infections begin to
occur and at one year of age eczema becomes present. Affected individuals
generally use to die by the age of ten but more recently prognosis has
generally improved (Fundenberg, 1980).

Patients have normal number of cells that react with anti-T Cell antisera
although they exhibit a decreased percentage of spontaneous rosette forming
cells (Fundenberg, 1980). Studies of the humoral limb of the immune system
have shown that although these patients have normal test serum immunoglobulin
levels, the class distribution is decidedly abnormal. IgE is markedly
elevated, IgA and IgD may also be elevated, IgG is normal and IgM is
decreased (Freedman, 1976).

The metabolism of these immunoglobulins is also abnormal. There is a marked
increase in the catabolism of immunoglobulins as well as albumin and in order
to keep up with this elevated destruction, the synthetic rate of IgE is
elevated by about 300% and IgA about 500%, IgM synthesis is not increased and
hence the serum level of IgM is low (Thaler, 1977).

These patients have normal immunoglobulin bearing B Cells and well as normal
numbers of cells with Fc and complement receptors, however they are unable to
mount optimal antibody responses against specific antigens (Thaler, 1977).
These finding has led to the proposal that the defect in the Wiskott- Aldrich
syndrome resides in the afferent limb of the immune system, thus it has been
suggested that antigens are either not recognized by the patients immune
system or else are abnormally precessed and/or presented to the
immunocompetent cells (Fundenberg, 1980).

It has been reported that some patients have subnormal number of monocytes
bearing Fc receptors, and perhaps even greater interest is a report that
lymphocytes from infected patients spontaneously secrete a factor that
inhibits the activity of both normal macrophages and macrophages from the
Wiskott-Aldrich syndrome (Freedman, 1976).

As a reminder, it has been suggested that an antigen must first come in
contact with the macrophage population before it can induce an immune
response (Fundenberg, 1980).

Treatment involves administration of antibodies, frozen plasma infusion, and
even bone marrow transplant. The use of a transfer factor obtained from the
leucocytes of normal donors has been most encouraging. Fifty percent of the
patients show clinical improvement on transfer factor therapy (Thaler, 1977).

Transfer factor therapy has been reported to induce clearing of the
eczematous skin disease and rarely to reduce the bleeding tendency in
association with the increase in the peripheral platelet count (Fundenberg,
1980).

Thymoma

Recurrent infection may be the presenting sign if the thymoma is associated
with immunodeficiency. Infections takes place in the form sinopulmonary
infection, chronic diarrhea, dermatitis, septicemia, stomatitis, and urinary
tract infection. It has also been associated with muscle weakness, are
generative anemia, thrombocytopenia, diabetes, amyloidosis, chronic hepatitis
and the development of nonthymic malignancy (Fundenberg, 1980).

In no instance has the removal of the thymoma resulted in improvement of
immunodeficiency. The overall prognosis is poor and death secondary to
infection is common. Death may also be related to associated abnormalities
such as thrombocytopenia and generative anemia (Fundenberg, 1980).

Short-limbed Dwarfism

There are three types of short limbed dwarfism that exist. Type I is
associated with the combined immunodeficiency, type II with cellular
immunodeficiency and Type III with the antibody immunodeficiency (Freedman,
1976).

In short limbed dwarfism, associated with combined immunodeficiency, symptoms
of infection are identical to those seen in the severe combined
immunodeficiency disease. Susceptibility to viral, bacterial, fungal and
protozoal infection is observed. Patients with this immundeficiency usually
die in their first year (Fundenberg, 1980).

Nucleoside Phosphorylase

Following the description of the ADA deficiency, many patients with various
immunodeficiences have been screened for other types of enzymatic defects of
purine metabolism. One young girl whose red cells lack any nucleoside
phosphorylase activity and this defect has been found in other
immunodeficient individuals. She's had recurrent infections (otitis media
and pneumonia) and diarrhea and also persistent anemia, her immunologic
status is severely compromised (Thaler, 1977). She has marked lymphopenia
with decreased percentage of spontaneous rosette forming cells. Poor T cell
function is evident in her inability to respond to PHA or allogenic cells and
her failure to exhibit positive skin tests. B cell function appears to be
intact, serum immunoglobulin seems to be normal and her cells mount adequate
antibody responses against T Independent and T dependant antigens. This
means that her T helper function is normal but her T effector function is
lost (Thaler, 1977).

Both parents of the child, who are cousins have only half the normal activity
of nucleoside phosphorylase and are probably heterozygotes, suggesting that
the defect is inherited as an autosomal recessive trait. Nucleoside
phosphorylase converts inosine to hypaxthine, the step following the reaction
requiring ADA activity in the catabolism of adenosine. This may them produce
biochemical abnormalities similar to ADA deficiency (Thaler, 1977).

Only red cell transfusions appear to improve the patients success in handling
infections (Fundenberg, 1980).

GVH

Graft-Versus-Host (GVH) Disease occurs when there is an unopposed attack of a
histo-incompatible cells on an individual who is unable to reject foreign
cells. There are three requirements for the disease. There must be
histocompatibility differences between host and donor. The graft cells must
be immunocompetent, and the host cells must be immunodeficient. The disease
can be a result of transfusion of blood or blood products containing
lymphocytes. The reaction may occur in three different forms, acute,
hyperacute and chronic, depending on their severity (Fundenberg, 1980).

Phagocytotic Dysfunctions

CGD

Chronic granulomatous disease is a defect of phagocytosis that inhibits the
phagocytic cells of the immune system from digesting microorganisms which
they have ingested. More specifically, the phagocytes are incapable of
forming oxygen radicals (O2-) and hydrogen peroxide. This causes a
cell-mediated response to the intracellular antigens and granulomas form.
Symptoms include pneumonia, lymphadenitis (infections in the lymph nodes) and
lesions in the skin, liver and other viscera (Roitt, 1993).

Myeloperoxidase Deficiency

Patients with this deficiency lack neutrophil and monocyte myeloperoxidase.
This enzyme performs intracellular bactericidal activity. In the healthy
situation the cell's lysosome will fuse to the phagosome and myeloperoxidase,
or some other catalase from peroxisomes will aid in the destruction of the
phagocytosed particle. Of course if the myeloperoxidase is absent the
phagocyte will not be able to efficiently digest and destroy the ingested
bacteria (Fundenberg, 1980).

Chediak-Higashi Syndrome

Visible signs of this disease include a deficiency in polymorphonuclear
granulocytes (neutropenia). These phagocytic cells also have abnormally
large granules, and the chemotactic responses of these cells are reduced.
The main defect seems to lie in the abnormality of some membrane bound
intracytoplasmic organelles, affecting the ability of the phagocytes to kill
intracellular, ingested bacteria (Fundenberg, 1980).

Symptoms include oculocutaneous (eye-related) albinism, and increased
susceptibility to pyogenic infections (Fundenberg, 1980).

Job's Syndrome

This syndrome may be a variation on Chronic Granulomatous Disease, since some
of the same phagocytic defects are similar. As in CGD the ingested bacteria
are not digested properly. Symptoms include recurring cold abscesses and
rashes similar to those caused by eczema. Patients for some reason have
generally been fair-skinned, red-haired females (Fundenberg, 1980).

Lazy Leucocyte Deficiency

This deficiency is also called Leucocyte Adhesion Deficiency, and involves a
defect in the CR3 receptor on the phagocyte. This receptor binds the C3b
receptor on the opsonized microorganisms (Roitt, 1993). The deficiency
therefore leads to the inability of the phagocyte to recognize the foreign
antigen. Lymphocyte function associated antigen (LFA-1) , important in cell
adhesion is also defective in these patients. This keeps phagocytes from
being able to adhere to the vascular endothelium and therefore they cannot
migrate out of blood vessels to the sites of infection when necessary
(Fundenberg, 1980). Symptoms include severe bacterial infections, especially
in the mouth and gastrointestinal tract (Roitt, 1993).

Complement Abnormalities

Deficiencies in all the complement proteins have been diagnosed in humans.
These generally lead to increased susceptibility to infections since the
complement cascade (opsonization, chemotaxis and lysis) may all be retarded
(Roitt, 1993).

C1q: Abnormalities

This complement protein is responsible for binding antibody. Deficiencies
have been noticed in patients with X-linked agammaglobulin and SCID and can
lead to immune-complex diseases, such as systemic lupus erythematosus
(Fundenberg, 1980).

C1r & C1s: Abnormalities

In the complement cascade these bind to C1q (Roitt, 1993). If a defect is
present C4 protein will not be cleaved and the cascade will not progress any
further. This deficiency is characteristic of patients experiencing
susceptibility to autoimmune diseases (systemic lupus erythematosus) and
bacterial infections (Fundenberg, 1980).

C2: Abnormalities

This protein must bind to surface bound C4b and in turn forms C3 convertase.
As in the above deficiencies the cascade ends and similar symptoms are
evident (Fundenberg, 1980).

C3: Abnormalities

C3 is important in opsonization of pyogenic bacteria (Roitt, 1993). A
deficiency shows a marked decrease in C3 in the serum. A lack of C3 means a
lack of C3a (anaphylatoxin) and C3b (for C5 convertase and opsonin) and
recurrent bacterial infection occurs (Fundenberg, 1980).

C4: Abnormalities

This protein is cleaved by C1s in the initial steps of the complement
cascade. Deficiency leads to similar symptoms as above.

C5,6,7,8,9: Abnormalities

The terminal component deficiencies as well as Factor H, Factor I, Factor D,
and properdin lead to increased pyogenic infection especially to N.gonorrheae
and N.meningitidis (Fundenberg, 1980).

HAO

Hereditary Angioneurotic Oedema is a result of a deficiency of the C1
inhibitor which binds to C1r and C1s to dissociate C1. Symptoms involve
recurrent episodes of swelling in various regions of the body. These regions
can be the intestines and the upper airway. If the classical pathway is not
regulated by C1 inhibitor then certain products (C2 kinin, bradykinin) cause
formation of gaps on post-capillary venules to allow plasma leakage. The
result of this is swelling (Roitt, 1993).

There are two types of Hereditary Angioneurotic Oedema known. The first type
involves a defect in the C1 inhibitor gene to keep transcripts from being
produced. In the second, point mutations present in the C1 inhibitor gene
cause defective molecules to produced (Roitt, 1993).

Secondary Immunodeficiencies

Secondary immunodeficiency diseases are those caused by extrinsic and
environmental causes.

Drugs used in chemotherapy cause a huge decrease in the number of T-cells in
the body. Protein malnutrition affects the immune system of children
throughout the world. In inflammatory bowel disease, huge losses of
immunoglobulin within the bowel can cause humoral immunodeficiency. Severely
damaged skin such as in burn victims can also lead to a huge decrease of
immunoglobulins. One of the most serious problems plaguing mankind at the
present is AIDS, an infection which parasitizes the cells of the immune
system (Roitt, 1993).

Immunodeficiency: Glossary

ABSCESS: collection of pus surrounded by an inflamed area in any
tissue or organ of an animal.

ADDISON'S DISEASE: a disease caused by deficiency of
adrenocorticosteroid hormones produced by cells of the adrenal
gland cortex. Adrenal antibodies are responsible for this
condition, characterized by low blood pressure, low blood-sugar,
reduced kidney function, weight loss, and weakness.

ALLOGRAFT: a transplant from one individual to another of the same
species but having different genotype. It is then subject to
rejection because of its foreign antigens.

ATOPIC disease: abnormal state of hypersensitivity which unlike
normal hypersensitivity is genetically determined. It can
involve the skin, respiratory system, intestinal and urinary system
and some vascular involvement.

ATROPHY: reduction in size of a tissue mass or organ, sometimes
because of lack of use.

AUTOIMMUNITY: conditions characterized by immunity to self
antigens, termed autoantigens. The body reacts adversely to its
own "self" tissues or cells.

CONGENITAL: existing at or before birth and referring especially to
defects and diseases that are environmental in origin and not
inherited.

DERMATITIS: eczematous disease (skin rash)

DERMATOMYOSITIS: an inflammatory disease of the muscles
accompanied by cutaneous symptoms.

ECZEMA: a skin rash, usually due to an allergy. It has varying
degrees of severity from swelling to scale-forming.

ENTEROPATHY: a disease associated with the intestinal mucosa and an
inflammatory infiltrate in the lamina propria. It can lead to
malabsorption and malnutrition as the intestine functions
improperly.

GAMOPATHY: a disorder involving abnormalities of immunoglobulins.

HAEMOLYTIC ANEMIA: a red blood cell disorder in which factors of
the immune system (complement, immunoglobulin) can affect the
number of cells, their volume, or their haemoglobin content.

HAEMOTOPOIETIC HYPOPLASIA: disorder resulting in decreased
production of red blood cells in the bone marrow. It is also
referred to Diamond-Blackfan Syndrome and is caused by production
of serum antibodies which act against bone marrow erythroblasts.
The result is anemia.

HYPOPARATHYROIDISM: in endocrine disease, involving parathyroid
failure. It is characterized by lymphocyte infiltration of the
parathyroid glands.

ISOAGGLUTININS: antibodies to major red cell agents that are
present in members of one species that can also be directed against
antigenic determinants on red cells of other members of the same
species.

LYMPHOPENIA: disorder in which there is a decrease in the number of
normally functioning lymphocytes.

MALIGNANCY: any condition has a tendency to spread and recur after
removal (cancerous).

MENINGITIS: inflammation of the meninges (membranes covering the
central nervous system) caused by infection.

MITOGEN: a growth factor in the form of a small protein found in
blood serum that often has a specific target organ in which it
induces mitosis.

NEONATE: referring to the first month of life, usually of a human

NEOPLASIA: development of growth of tissue in the body that has no
apparent function (tumour).

NEUTROPENIA: disorder characterized by a decrease of normally
functioning neutrophils.

PERNICIOUS ANEMIA: disorder in which the glands of the body of the
stomach are destroyed leading to loss of acid, pepsinogen, and
others. Immediate symptoms include weakness, weight loss and
appetite loss.

PNEUMONIA: a disease of the lungs in humans caused by
Streptococcus pneumonia and other viral pathogens.

PYOGENIC: pus-producing, a yellow fluid consisting of serum, white
blood cells, bacteria, and tissue debris formed during the
inflammation process.

RHEUMATOID ARTHRITIS: disorder in which the cell-mediated
mechanisms of the immune system are directed against autoantigens
(self antigens) causing chronic, damaging inflammation. In this
case it occurs in the joints.

ROSETTE: a cluster of erythrocytes bound by an antibody producing
cell.

SLE: Systemic Lupus Erythematosus, a chronic systemic
inflammatory autoimmune disease. It involves decreased
complement in the serum and antibodies developed to double
stranded DNA, and sometimes T lymphocytes.

THROMBOCYTOPENIA: this is a disorder characterized by decreased
number of platelets in the blood.

THYMIC HYPOPLASIA: this is simply another term for DiGeorge
Syndrome.

ULCERATIVE COLITIS: chronic inflammatory disease of the mucosa of
the colon. As in enteropathy infiltration of the lamina propria by
mononuclear inflammatory cells occurs. Diarrhea, and
dehydration can occur.

General Clinical Features

A. Features Frequently Present and Highly Suspicious:

1. Chronic infection
2. Recurrent infection (more than expected)
3. Unusual infecting agents
4. Incomplete clearing between episodes of infection or
incomplete response to treatment
(Fundenberg, 1980)

B. Features Frequently Present and Moderately Suspicious:

1. Skin rash (eczema, Candida, etc.)
2. Diarrhea (chronic)
3. Growth failure
4. Hepatosplenomegaly
5. Recurrent abscesses
6. Recurrent osteomyelitis
(Fundenberg, 1980)

C. Features Associated With Specific Immunodeficiency Disorders

1. Ataxia
2. Telangiectasia
3. Short-limbed dwarfism
4. Cartilage-hair hypoplasia
5. Idiopathic endocrinopathy
6. Partial albinism
7. Thrombocytopenia
8. Eczema
9. Tetany
(Fundenberg, 1980)

Treatment of Immunodeficiencies

GAMMA GLOBULIN:

B-Cell Disorders: X-linked hypogammaglobulinemia.
Acquired hypogammaglobulinemia.
Secondary hypogammaglobulinemia when associated
with infection. Do not use in selective IgA
deficiency.
T-Cell Disorders: Use only when absent antibody response is
demonstrated. Not recommended for Wiskott-
Aldrich syndrome.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

HYPERIMMUNE GAMMA GLOBULIN:

B-Cell Disorders: Use in above disorders when specific exposure
has occurred.
T-Cell Disorders: May be used when specific exposure has
occurred.

Phagocytic Disorders: May be used
when specific exposure has occurred.
Complement Disorders: May be used when specific exposure has
occurred.
(Fundenberg, 1980)

FROZEN PLASMA BY INTRAVENOUS INFUSION:

B-Cell Disorders: X-linked hypogammaglobulinemia and acquired
hypogammaglobulinemia when intramuscular
administration is not tolerated or is
ineffective.
T-Cell Disorders: Use only when absent antibody response is
demonstrated. Irradiate to prevent GVH.
Phagocytic Disorders: Not recommended.
Complement Disorders: Use with caution. Plasma may exacerbate
autoimmune disease.
(Fundenberg, 1980)

INFUSIONS OF WHITE CELLS:

B-Cell Disorders: Not recommended
T-Cell Disorders: Not recommended
Phagocytic Disorders: Questionable value
Complement Disorders: Not recommended
(Fundenberg, 1980)

INFUSIONS OF RED CELLS

B-Cell Disorders: Not recommended
T-Cell Disorders: May be of benefit in certain enzyme
deficiencies associated with immunodeficiency
(adenosine deaminase, purine nucleoside
phosphorylase). Irradiate to prevent GVH.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

BONE MARROW TRANSPLANT

B-Cell Disorders: Not recommended
T-Cell Disorders: Use only when impaired T-Cell function is
present. Must have histocompatible donor.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

FETAL THYMUS TRANSPLANTATION

B-Cell Disorders: Not recommended
T-Cell Disorders: DiGeorge syndrome. Severe combined
immunodeficiency without suitable bone marrow
donor. Selective use in other combined
immunodeficiency disorders.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

CULTURED THYMUS EPITHELIUM

B-Cell Disorders: Not recommended
T-Cell Disorders: Selective cases of T-Cell disorders where no
suitable bone marrow donor is available.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

FETAL LIVER TRANSPLANTATION

B-Cell Disorders: Not recommended
T-Cell Disorders: Sometimes used in severe combined
immunodeficiency in absence of suitable bone
marrow donor.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

TRANSFER FACTOR

B-Cell Disorders: Not recommended
T-Cell Disorders: May be successful in chronic candidiasis when
combined with antifungal agent. Highly
debatable effect in other disorders.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

THYMOSIN AND OTHER THYMIC FACTORS

B-Cell Disorders: Not recommended
T-Cell Disorders: Limited evaluation to date. May enhance T-cell
function in a variety of T-cell disorders,
including DiGeorge syndrome. No effect in
chronic candidiasis or severe combined
immunodeficiency.
Phagocytic Disorders: Not recommended
Complement Disorders: Not recommended
(Fundenberg, 1980)

Immunodeficiency: References

Amos, Bernard Immune Mechanisms and Disease, New York, New York, Academic
Press Inc., 1977

Amos, Bernard Progress in Immunology, New York, New York; Academic Press
Inc., 1972

Bellanti, Joseph A. M.D. Immunology, Philidelphia, Pennsylvanaia; W.B.
Saunders Company, 1971

Broder, Samuel AIDS: Modern Concepts and Therapeutic Challenges, New York,
New York, Marcel Dekker Inc., 1987

Freedman, Samuel O. and Gold, Phil Clinical Immunology, 2nd ed, Hagerstown,
Maryland; Harper and Row Publishers, 1976.

Fundenberg, Hugh H. M.D. et al, Basic and Clinical Immunology, Los Altos,
California; LANGE Medical Publications., 1980

Roitt, Ivan M., Brostoff, Johnathan and Male, David K. Immunology London,
England, Mosby-Year Book Europe Limited, 1993

Silverstien, Arthur M. A History of Immunology, San Diego, California;
Academic Press Inc., 1989

Thaler, Malcolm S. M.D., Klausner, Richard D. M.D. and Cohen, Harvey J. M.D.
Medical Immunology, Philidelphia, Pennsylvania; J.B. Lippincott Company,
1977.