Microbiology and Immunology

WORLD OF MICROBIOLOGY AND IMMUNOLOGY Immunodeficiency diseases, genetic causes

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ferent germs. Some of these diseases are relatively mild with

onset in adolescence or adulthood. Others are severely debil-

itating and severely compromise daily activity. Clinically

significant primary immunodeficiencies are relatively rare

with 1 in 5,000 to 1 in 10,000 people in developed countries

afflicted.

The most common form of primary immunodeficiency,

selective IgA deficiency, is a very mild deficiency and may

affect as many as 1 in every 300 persons, most of whom will

never realize they have an immunodeficiency at all. B-cells

are lymphocytes that produce antibodies and this component

of the immune system is often called humoral immunity.

Defects in humoral immunity predispose the body to viral

infections. T-cells are lymphocytes that are processed in the

thymus gland. Granulocytes are cells which consume an

destroy bacteria.

There are now thought to be around 70 different primary

immunodeficiency diseases. Of the more common forms, the

vast majority of these conditions are recessive. This means that

a single working copy of the geneis generally sufficient to per-

mit normal immune functioning. Some of the genes are found

on the X chromosome. Since males receive only a single X

chromosome, recessive mutationsof these genes will result in

disease. Females have two copies of the X chromosome, and so

rarely will express X-linked recessive diseases.

The most widely known of the primary immunodefi-

ciencies is severe combined immune deficiency (SCID) and it

conjures pictures of a child who must live his life encased in

a plastic bubble to keep out germs. SCID is manifest in early

childhood as a severe combined T cell and B cell deficiency,

and can be caused by a number of different gene mutations.

The most common form is X-linked, and so primarily affects

boys. It can also be caused by an enzyme called adenosine

deaminase. When ADA is deficient, toxic chemicals kill off

the lymphocytes. Until recently, SCID was uniformly lethal.

In recent years, the elucidation of the genes responsible has

made possible interventions based on gene therapy. SCID

often presents in early childhood as persistent diaper rash or

thrush. Pneumonia, meningitis, blood poisoning, and many

common viral infections are serious threats to children born

with SCID. Diagnosis demands immediate medical attention

and bone marrow transplants are a common form of treatment

for SCID. Children with ADA deficiency may be treated with

ADA infusions to correct the enzyme deficiency. Partial com-

bined immune deficiencies are milder conditions in which

cellular and humoral immunity are both compromised but not

completely shut down. These are generally accompanied by

other physical symptoms and so constitute syndromes.

Wiskott-Aldrich syndrome, for example, is an X-linked par-

tial combined syndrome in which the repeated infections are

combined with eczema and a tendency toward bleeding.

Another combined B and T cell deficiency is ataxia telang-

iectasia (AT). In AT, the combined B and T cell deficiency

causes repeated respiratory infections, and is accompanied by

a jerky movement disorder and dilated blood vessels in the

eyes and skin. The thymus gland where T-cells are processed

is underdeveloped.

Deficiency of the B cell population results in decreased

antibodyproduction and thus, an increased risk of viral or bac-

terial infection. X-linked agammaglobulinemia (XLA) is a

condition in which boys (because it is X-linked) produce little

to no antibodies due to an absence of B cellsand plasma cells

in circulation. As these children grow, they deplete the anti-

bodies transmitted through the mother, and they become

susceptible to repeated infections. Common variable immun-

odeficiency (CVID) is a group of disorders in which the num-

ber of B cells is normal, but the levels of antibody production

are reduced.

DiGeorge anomaly is an example of a T cell deficiency

produced by an underdeveloped thymus gland. Children with

DiGeorge anomaly often have characteristic facial features,

developmental delays, and certain kinds of heart defects usu-

ally stemming from small deletions on chromosome 22 (or

more rarely, chromosome 10). In rare cases, there is an auto-

somal dominant gene mutation rather than a chromosome

deletion.

Phagocytosis, the ability of the granulocytes to ingest

and destroy bacteria, can also be the chief problem. One

example of this is chronic granulomatous disease (CGD).

There are four known genes that cause CGD; all are reces-

sive. One is on the X chromosome, and the other three are on

autosomes. These children do well until around age three

when they begin to have problems with staphylococcal infec-

tions and infections with fungiwhich are generally benign in

other people. Their granulosa cells may aggregate in tissues

forming tumor like masses. Similarly, leukocyte adhesion

defect (LAD) is a condition in which granulocytes fail to

work because they are unable to migrate to the site of infec-

tions. In Chediak-Higashi syndrome (CHS), not only granu-

locytes, but also melanocytes and platelets are diminished.

CHS is generally fatal in adolescence unless treated by bone

marrow transplantation.

One other class of primary immunodeficiencies, the

complementsystem defects, result from the body’s inability to

recognize and/or destroy germs that have been bound by anti-

bodies. Complement fixation is a complex multi step process,

and thus a number of different gene mutations can potentially

corrupt the normal pathway. Complement system defects are

rare and often not expressed until later in life.

The prospect of the development of effective and safe

gene therapies holds hope for the primary immunodeficiency

diseases. As these genes and their genetic pathways are more

fully understood, interventions which replace the missing gene

product will likely provide effective treatments.

See alsoImmunity, cell mediated; Immunity, humoral regula-

tion; Microbial genetics; Microbiology, clinical

IMMUNOELECTRON MICROSCOPY,

THEORY, TECHNIQUES AND USES •see

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