Excerpt from Immunoglobulin G Deficiency

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Background

Immunodeficiency diseases are commonly classified into disorders that affect one or more of the 4 major limbs of the immune system. These limbs are (1) B cells, ie, humoral immunity; (2) T cells, ie, cell-mediated immunity; (3) phagocytes; and (4) complement.

B-cell immunity is mediated by the immunoglobulins and is commonly referred to as humoral immunity. Humoral immunity is differentiated from T-cell immunity, which is commonly referred to as cellular immunity, and from phagocytic cell immune function. Immunoglobulins, which are protein molecules that contain antibody activity, are produced by the terminal cells of B-cell differentiation known as plasma cells. Immunoglobulins have important roles in humoral immunity, and they consist of 5 major classes or isotypes: immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), immunoglobulin D (IgD), and immunoglobulin E (IgE). The most abundant immunoglobulin class is IgG (73%), which has a molecular weight of 150 kd (see Image 1). IgG is present in plasma and external secretions and is expressed on the B-cell membrane.

IgG is further subdivided into 4 subclasses: IgG1, IgG2, IgG3, and IgG4 (see Image 2). Fortunately, for ease of recall, the serum concentrations of the subclasses directly correlate with their numerical nomenclature such that IgG1 is found in greater concentrations than IgG2 and so forth.

A deficiency in a tyrosine kinase designated as Bruton tk, in honor of Bruton, was discovered. In 1952, Bruton described classic B-cell deficiency in an 8-year-old boy with X-linked agammaglobulinemia. The patient presented with frequent pyogenic infections, and all 5 major immunoglobulin isotypes were undetectable. In the early 1960s, following the discovery of the IgG subclasses, certain associations were also recognized between individual subclass deficiencies and recurrent infection. IgG deficiencies may occur as isolated deficiencies (eg, selective IgG deficiency) or in association with deficiencies of other immunoglobulin types (eg, combined immunodeficiency). Moreover, IgG subclass deficiencies may be observed even if the total IgG concentration is normal.

Pathophysiology

B and T cells are responsible for specific immunity, otherwise known as adaptive immunity. Abnormal production of these cells may be observed in clinical states in which production is atypically excessive (eg, lymphoproliferative diseases such as lymphoma and leukemia) or in immunodeficiency disorders in which production is aberrantly low.

IgG exists in both intravascular and extravascular spaces and is important in the secondary antibody responses (immune memory). It plays an important role in host defense against infection. IgG protects tissues from bacteria, viruses, and toxins. Different subclasses of IgG neutralize bacterial toxins, activate complement, and enhance phagocytosis by opsonization (Beers, 2004).

Importantly, note that a low IgG level, with normal IgA and IgM levels, does not necessarily equate with antibody deficiency. The evaluation of specific antibody responses is essential for the diagnosis and for appropriate treatment.

For ease of discussion, IgG deficiencies may be divided into 2 categories. The first is selective IgG deficiency, which consists of an isolated deficiency of IgG with normal levels of IgA, IgM, IgD, and IgE. The second is combined IgG deficiency, which manifests as a deficiency of IgG accompanied by inadequate levels of other immunoglobulin isotypes. This must be differentiated from common variable immunodeficiency (CVI).

These disorders occur in persons of any age or sex. Immunoglobulin deficiencies were previously referred to as late-onset agammaglobulinemia, and now they are classified as hypogammaglobulinemia syndromes. Both pediatric and adult populations may be affected by a group of unclassified antibody deficiencies that is considered a form of CVI. See Common variable immunodeficiency for more details.

IgA deficiency is the most common immune deficiency, and approximately 20% of patients also show a lack of IgG2 and IgG4. These individuals have greater risk of infection than patients with either isolated IgA or IgG deficiency.

Frequency

United States

Although the frequency of isolated IgG deficiency is not known with certainty, IgG subclass deficiency is probably more common and occurs in families with CVI. Some reports indicate that the prevalence of IgG deficiency may be 1 case per 10,000 persons. However, the frequency of IgG subclass deficiencies varies according to geographic area, although they are more common than other immunodeficiencies.

Mortality/Morbidity

• Early diagnosis and treatment of IgG deficiency is essential to prevent and control both morbidity and mortality.
• IgG subclass deficiencies are highly variable, even within an affected individual. Additional deficiencies may develop as a result of switching between different IgG subclasses.

Sex

• Males and females are affected.

Age

• Children and adults are affected. Children cannot make IgG2 until aged at least 24 months; hence, measuring the IgG2 subclass concentration before this age is not meaningful.
• The most common subclass deficiency in early childhood is IgG2 deficiency; in adults, IgG3 deficiency is predominant. IgG1 levels in children are usually higher than in adults.
• Although children rapidly attain adult levels of IgG1 and IgG3, the development of IgG2 and IgG4 is slower (see Image 3). In some children, this period of maturation may take 16 years before full attainment of adult levels.

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