Page 491 - Clinical Immunology_ Principles and Practice ( PDFDrive )

34

Primary Antibody Deficiencies

Tracy Hwangpo, Harry W. Schroeder, Jr.

Primary antibody deficiency diseases are characterized by an CLINICAL PEARLS
inability of the humoral immune system to produce sufficient
quantities of protective antibodies to properly protect the host Clinical Manifestations of Antibody Deficiency
1
from hazardous antigens. This inability may be evident from • Recurrent bacterial infections
birth, or it may manifest at a later age. In some cases, the deficiency • Early in untreated disease, infections are primarily caused by
2
may either resolve or worsen with time. Many of these diseases encapsulated pyogenic bacteria (e.g., Streptococcus pneumoniae
are caused by mutations that alter the function of genes that and Haemophilus influenzae type b).
regulate B-cell development or homeostasis. Others reflect • Later in untreated disease, damage to mucosal surfaces engenders
mutations in the immunoglobulin (Ig) genes themselves. In some susceptibility to staphylococci, nontypable H. influenzae, and gram-
negative rods, as well.
of the most common conditions, a genetic predisposition has • Recurrent viral infections
been well documented, but the underlying defect remains unclear. • In most cases, viral infections are cleared normally, but protective
The typical patient will present with a history of recurrent upper immunity does not develop. For example, recurrent shingles can
or lower respiratory infections and reduced serum concentrations be a common symptom in untreated patients.
of one or more classes of immunoglobulin (IgM, IgG, or IgA). • In some cases, patients may continue to excrete virus after resolution
However, patients with normal serum Ig levels may exhibit specific of their clinical symptoms.
deficits in their ability to mount a protective response against • Increased prevalence of other immunological disorders
• Paradoxical increased risk of antibody-mediated autoimmune dis-
certain antigens, and some patients with agammaglobulinemia orders, such as idiopathic thrombocytopenia, autoimmune thyroiditis,
can be remarkably asymptomatic. A classification of primary systemic lupus erythematosus, and celiac disease.
antibody deficiency diseases can be found in Table 34.1. • Lymphoid hypertrophy
Primary immune deficiency disorders are the consequence • Increased risk of allergic disorders, especially among patients with
of specific defects in B-cell development (Chapter 7). B-cell IgA deficiency.
production begins in the fetal liver and shifts to bone marrow
in the latter stages of fetal life (Fig. 34.1). As B cells mature, they
leave the liver and bone marrow and migrate via blood into patients that are deficient in neutrophil function or in the pivotal
secondary lymphoid organs, including spleen, lymph nodes, and third component of complement (C3), all three of these arms
other peripheral and mucosal tissues. Contact with a polymeric of the host defense system should be evaluated in patients who
cognate antigen, such as a polysaccharide, can activate the B cell suffer with recurrent bacterial infections.
and allow it to differentiate into an antibody-producing plasma The clinical course of uncomplicated primary infections with
cell. In contrast, the response to protein antigens, including toxins viruses, such as varicella zoster or mumps virus, does not differ
and viral proteins, requires T-cell help. In the germinal centers, significantly from that of the normal host. However, patients
B cells can replace an upstream heavy (H) chain constant domain with antibody deficiency have difficulty generating long-lasting
with a downstream one (e.g., µ to γ1), altering effector function immunity; thus chickenpox can repeatedly recur as shingles.
(Chapter 15). They can also introduce mutations at a high level The general rule is that T cells typically control established viral
into the variable (V) domains, tailoring the antibody to the infections, whereas antibodies limit initial viral dissemination
antigen, a process termed affinity maturation. and cell entry, thereby preventing reinfection. As with all rules,
there are exceptions. Patients with hypogammaglobulinemia can
CLINICAL MANIFESTATIONS have difficulty clearing hepatitis B virus from the circulation,
poliovirus from the gut, and enterovirus from the brain, leading
Patients with antibody deficiencies most commonly present with a to progressive and sometimes fatal outcomes.
history of recurrent sinusitis, bronchitis, and pneumonia. Patients Because sinopulmonary infections are also commonly seen
can also present with recurrent cellulitis, boils, gastrointestinal in normal infants and children, in individuals with allergies, in
(GI) discomfort, myalgias, arthralgias, fatigue, and depression. smokers, and in patients with other diseases, such as cystic fibrosis,
The respiratory infections typically involve encapsulated bacterial the threshold for an extensive evaluation for immunodeficiency
pathogens, such as Streptococcus pneumoniae and Haemophilus can be a matter of clinical judgment. However, two or more
influenzae. Protection against these bacteria requires production episodes of bacterial pneumonia within a 5-year period, unex-
of antipolysaccharide antibodies, which does not require T-cell plained bronchiectasis, H. influenzae meningitis in an older child
help. Because a similar susceptibility for infection is seen among or adult, chronic otitis media in an adult, recurrent intestinal

471