Author and Editor Disclosure

Synonyms and related keywords: IgD deficiency, immunodeficiency syndrome, hypoimmunoglobulinemia D, hypogammaglobulinemia D, dysimmunoglobulinemia D, dysgammaglobulinemia D, selective IgD deficiency, common variable immunodeficiency

Background

Immunoglobulin D (IgD) deficiency is a defect of humoral immunity that is characterized by abnormally low serum levels of IgD immunoglobulins. Little is known about the normal function of IgD, and few clinical signs or symptoms are associated with its absence. Individuals with low or absent levels of IgD do not appear unusually predisposed to infections.

Pathophysiology

Genetic rearrangements occur during the maturation of B lymphocytes, eventually resulting in the surface expression of both immunoglobulin M (IgM) and IgD on mature B cells. Cell signaling occurs through this surface IgD. IgD production by B cells is stimulated by interleukin (IL)–4 and IL-10.¹

The physiologic purpose of free serum IgD is not well understood. In mice, IgD may substitute for some functions of IgM when IgM is absent. Studies in IgM-deficient IgM^-/- mice reveal that B cells with surface expression of IgM were replaced by B cells with surface expression of IgD. Immunization of IgM^-/- mice revealed an IgD immune response in place of the now absent IgM response, although with a delayed increase in antibody concentration as compared to normal.²

Low serum IgD levels are not distributed in a normal gaussian fashion.^{3, 4} IgD deficiency is associated with the specific human leukocyte antigens HLA-B18, F1C30, and DR3 in a Spanish Basque population⁵ and HLA-B8, SC01, DR3 in white subjects in an American study.⁶

Frequency

United States

One report indicates that approximately 11% of 371 American Red Cross blood donors and 6% of 1529 study subjects had low or undetectable IgD levels (<0.002 mg/mL). In the study group, a number of the individuals with low IgD had rheumatologic disease (eg, juvenile rheumatoid arthritis, lupus, psoriatic arthritis, vasculitis), but the frequency of low IgD within groups of patients with each disease did not differ from the normal controls using chi-square analysis.⁴ In another study, using a cutoff of 2.15 IU/mL, assays of 245 healthy adults and 301 healthy children revealed that approximately 13% of each group had low levels of IgD.³

Mortality/Morbidity

Low or undetectable levels of IgD, in the absence of other concurrent disease or immune defects (eg, common variable immunodeficiency, complement deficiency), are not associated with morbidity or increased mortality. Specifically, patients with low or undetectable IgD levels do not demonstrate an increased incidence of infections of any type.⁷

Sex

Overall levels of serum IgD are higher in males than females,⁸ but specific incidence of abnormally low IgD is approximately equal between the sexes.³

Age

Children younger than 3 years, both with and without an immunodeficiency, appear to have an increased prevalence of low IgD levels.^{9, 10, 11} After infancy, age is not associated with increased prevalence of low IgD levels.³

History

• No specific signs or symptoms are associated with isolated IgD deficiency; therefore, this condition is usually discovered incidentally during immunological laboratory testing (eg, quantitative serum immunoglobulin levels).

Physical

• A patient with low IgD levels but no concurrent immunoglobulin deficiencies of other classes or other immune defects typically does not develop specific physical findings associated with low or absent IgD levels.

Causes

• Family studies from one report indicate that low serum IgD levels may be inherited in an autosomal recessive fashion.³
• Another study found several families with possible characteristics of autosomal recessive inheritance, and other families with a pattern more consistent with multiple allele involvement. This latter report also suggested an increased frequency of certain HLA antigens in individuals with low IgD levels.⁴
• An HLA association has also been seen in a Basque population, which suggested a partially penetrant dominant susceptibility gene for IgD deficiency.⁵ These findings have been further supported in another recent study.⁶

Hypogammaglobulinemia
Immunoglobulin A Deficiency

Other Problems to be Considered

Agammaglobulinemia
Common variable immunodeficiency
Severe combined immunodeficiency
Hyperimmunoglobulin M syndrome
Other humoral immunodeficiencies

Lab Studies

• Measure all classes of quantitative immunoglobulin levels (eg, immunoglobulin A [IgA], immunoglobulin G [IgG], IgM, immunoglobulin E). However, quantification of the IgG subclass is usually not necessary. Measuring these levels helps exclude a more extensive humoral immunodeficiency (eg, common variable immunodeficiency, IgA deficiency); low levels of IgD may be associated with the presence of other immune disorders.^{12, 13}
• Consider screening laboratory testing for complement disorders (eg, CH50), as well.¹⁴

Imaging Studies

• Imaging studies are not routinely required for patients with isolated IgD deficiency.

Other Tests

• Other tests are not routinely required for patients with isolated IgD deficiency.

Procedures

• Procedures are not routinely required for patients with isolated IgD deficiency.

Medical Care

After excluding more extensive immunodeficiency, possibly with the assistance of an allergist or clinical immunologist, patients do not need further routine care. Longitudinal follow-up examinations with periodic quantitative immunoglobulin measurements and surveillance for immune, infectious, or rheumatologic disease are advised.

Surgical Care

Surgical measures are not a component of treatment.

Consultations

If a nonspecialist discovers the IgD deficiency, refer the patient to an allergist or clinical immunologist to help exclude other more serious related conditions.

Diet

Patients require no special diet.

Activity

Activity restrictions are not necessary.

Isolated IgD deficiency does not require treatment. Specifically, intravenous or subcutaneous immunoglobulin replacement therapy is not indicated. Such immunoglobulin replacement should be considered only if an associated immunodeficiency (eg, common variable immunodeficiency) is present, which is normally treated with immunoglobulin replacement. If immunoglobulin replacement therapy is indicated, see Hypogammaglobulinemia for detailed information on dosage, contraindications, drug interactions, and precautions.

Promptly treat any infections with appropriate antibiotics. Dosage, route, and duration of therapy depend on the suspected pathogen, specific drug chosen, and response to therapy. Check the monograph of a particular antibiotic for detailed information concerning contraindications, drug interactions, and precautions.

Further Outpatient Care

• Consider performing periodic (every 1-2 y) serial determinations of quantitative immunoglobulin (all classes) levels in patients with isolated IgD deficiency that was discovered incidentally.

In/Out Patient Meds

• Patients require no specific therapy.

Complications

• Routinely monitor patients for infections and autoimmune disease, although no reports indicate that these individuals are at increased risk. If infections develop, promptly treat patients with appropriate therapy.

Prognosis

• In the absence of comorbid conditions, prognosis is excellent.

Patient Education

• Educate patients about the humoral immune system and inform them that the specific function of IgD is not fully understood at this time. Request patients to promptly report any signs or symptoms of infection to their primary care provider.

Medical/Legal Pitfalls

• Failure to measure quantitative levels of other immunoglobulin classes (eg, IgA, IgG, IgM) to rule out more extensive and serious humoral immunodeficiency diseases (eg, common variable immunodeficiency) when discovering low or absent IgD levels

Special Concerns

• Special patient populations (eg, children, older individuals, pregnant women) with isolated IgD deficiency do not require specialized treatment.