eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

Immunoglobulin D Deficiency

Donald A Dibbern Jr, MD, Consulting Staff (Allergist), Providence St Vincent Medical Center
John M Routes, MD, Professor of Pediatrics, Medical College of Wisconsin; Chief, Section of Allergy and Clinical Immunology, Department of Pediatrics, Children's Hospital of Wisconsin

Updated: Dec 2, 2009

Introduction

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, though it may fine tune or modulate humoral immune response.^{[2 ]}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.^{[3 ]}Recent studies have suggested that IgD-only B cells may play a significant role in immune responses to superantigens.^{[4 ]}Investigations into the evolutionary origins of IgD are also ongoing.^{[5 ]}

Low serum IgD levels are not distributed in a normal gaussian fashion.^{[6,7 ]}IgD deficiency is associated with the specific human leukocyte antigens HLA-B18, F1C30, and DR3 in a Spanish Basque population^{[8 ]}and HLA-B8, SC01, DR3 in white subjects in an American study.^{[9 ]}A 2008 report noted that depletion of circulating IgD+ memory B cells occurs in pediatric HIV infection, despite control of viral load with highly active anti-retroviral therapy (HAART).^{[10 ]}

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.^{[7 ]}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.^{[6 ]}

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.^{[11 ]}

Sex

Overall levels of serum IgD are higher in males than females,^{[12 ]}but specific incidence of abnormally low IgD is approximately equal between the sexes.^{[6 ]}

Age

Children younger than 3 years, both with and without an immunodeficiency, appear to have an increased prevalence of low IgD levels.^{[13,14,15 ]}After infancy, age is not associated with increased prevalence of low IgD levels.^{[6 ]}

Clinical

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.^{[6 ]}
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.^{[7 ]}
An HLA association has also been seen in a Basque population, which suggested a partially penetrant dominant susceptibility gene for IgD deficiency.^{[8 ]}These findings have been further supported in another recent study.^{[9 ]}

Differential Diagnoses

Hypogammaglobulinemia
Immunoglobulin A Deficiency

Workup

Laboratory 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.^{[16,17 ]}
Consider screening laboratory testing for complement disorders (eg, CH50), as well.^{[18 ]}

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.

Treatment

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.

Medication

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.

Follow-up

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.

Inpatient & Outpatient Medications

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.

Miscellaneous

Medicolegal 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.

References

Levan-Petit I, Lelievre E, Barra A, et al. Th2 cytokine dependence of IgD production by normal human B cells. Int Immunol. 1999;11:1819-1828.
Geisberger R, Lamers M, Achatz G. The riddle of the dual expression of IgM and IgD. Immunology. Aug 2006;118(4):429-37. [Medline].
Lutz C, Ledermann B, Kosco-Vilbois MH, et al. IgD can largely substitute for loss of IgM function in B cells. Nature. 1998;393 (6687):797-801.
Seifert M, Steimle-Grauer SA, Goossens T, Hansmann ML, Brauninger A, Kuppers R. A model for the development of human IgD-only B cells: Genotypic analyses suggest their generation in superantigen driven immune responses. Mol Immunol. Feb 2009;46(4):630-9. [Medline].
Gambon-Deza F, Espinel CS. IgD in the reptile leopard gecko. Mol Immunol. Jul 2008;45(12):3470-6. [Medline].
Dunnette SL, Gleich GJ, Weinshilboum RM. Inheritance of low serum immunoglobulin D. J Clin Invest. Aug 1978;62(2):248-55. [Medline].
Fraser PA, Schur PH. Hypoimmunoglobulinemia D: frequency, family studies, and association with HLA. Clin Immunol Immunopathol. Apr 1981;19(1):67-74. [Medline].
Calvo B, Castano L, Marcus-Bagley D, et al. The [HLA-B18, F1C30, DR3] conserved extended haplotype carries a susceptibility gene for IgD deficiency. J Clin Immunol. May 2000;20(3):216-20. [Medline].
Alper CA, Marcus-Bagley D, Awdeh Z, et al. Prospective analysis suggests susceptibility genes for deficiencies of IgA and several other immunoglobulins on the [HLA-B8, SC01, DR3] conserved extended haplotype. Tissue Antigens. Sep 2000;56(3):207-16. [Medline].
Jacobsen MC, Thiebaut R, Fisher C, Sefe D, Clapson M, Klein N. Pediatric human immunodeficiency virus infection and circulating IgD+ memory B cells. J Infect Dis. Aug 15 2008;198(4):481-5. [Medline].
Sanal O, Ersoy F, Tezcan I, et al. Serum IgD concentrations in immunodeficiency diseases. Turk J Pediatr. Jul-Sep 1990;32(3):175-82. [Medline].
Mosedale DE, Sandhu MS, Luan J, Goodall M, Grainger DJ. A new sensitive and specific enzyme-linked immunosorbent assay for IgD. J Immunol Methods. 2006;313(1-2):74-80. [Medline].
Litzman J, Ward AM, Wild G, et al. Serum IgD levels in children under investigation for and with defined immunodeficiency. Int Arch Allergy Immunol. Sep 1997;114(1):54-8. [Medline].
Haraldsson A, Weemaes CM, Jonasdottir S, et al. Serum immunoglobulin D in infants and children. Scand J Immunol. Apr 2000;51(4):415-8. [Medline].
Josephs SH, Buckley RH. Serum IgD concentrations in normal infants, children, and adults and in patients with elevated IgE. J Pediatr. Mar 1980;96(3 Pt 1):417-20. [Medline].
Buckley RH, Fiscus SA. Serum IgD and IgE concentrations in immunodeficiency diseases. J Clin Invest. Jan 1975;55(1):157-65. [Medline].
de Laat PC, Weemaes CM, Bakkeren JA. Immunoglobulin levels during follow-up of children with selective IgA deficiency. Scand J Immunol. Jun 1992;35(6):719-25. [Medline].
Alper CA, Xu J, Cosmopoulos K, et al. Immunoglobulin deficiencies and susceptibility to infection among homozygotes and heterozygotes for C2 deficiency. J Clin Immunol. Jul 2003;23(4):297-305. [Medline].
Lee SK, Metrakos JD, Tanaka KR, et al. Genetic influence on serum IgD levels. Pediatr Res. Jan 1980;14(1):60-3. [Medline].
Levan-Petit I, Cardonna J, Garcia M, et al. Sensitive ELISA for human immunoglobulin D measurement in neonate, infant, and adult sera. Clin Chem. Jun 2000;46(6 Pt 1):876-8. [Medline].
Vladutiu AO. Immunoglobulin D: properties, measurement, and clinical relevance. Clin Diagn Lab Immunol. Mar 2000;7(2):131-40. [Medline].
Vladutiu AO, Netto D. Is quantitation of serum IgD clinically useful? [letter]. Clin Chem. Jun 1982;28(6):1409-10. [Medline].

Keywords

IgD deficiency, immunodeficiency syndrome, hypoimmunoglobulinemia D, hypogammaglobulinemia D, dysimmunoglobulinemia D, dysgammaglobulinemia D, selective IgD deficiency, common variable immunodeficiency

Contributor Information and Disclosures

Author

Donald A Dibbern Jr, MD, Consulting Staff (Allergist), Providence St Vincent Medical Center
Donald A Dibbern Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, and Oregon Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

John M Routes, MD, Professor of Pediatrics, Medical College of Wisconsin; Chief, Section of Allergy and Clinical Immunology, Department of Pediatrics, Children's Hospital of Wisconsin
John M Routes, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Microbiology, American Society for Virology, Clinical Immunology Society, and Federation of American Societies for Experimental Biology
Disclosure: Nothing to disclose.

Medical Editor

Melvin Berger, MD, PhD, Adjunct Professor of Pediatrics and Pathology, Case Western Reserve University; Senior Medical Director, Clinical Research and Development, CSL Behring, LLC
Melvin Berger, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Clinical Investigation, and Clinical Immunology Society
Disclosure: CSL Behring Salary Employment

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Michael R Simon, MD, MA, Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Adjunct Staff, Division of Allergy and Immunology, Department of Internal Medicine, William Beaumont Hospital
Michael R Simon, MD, MA is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, American Federation for Medical Research, Michigan Allergy and Asthma Society, Michigan State Medical Society, Royal College of Physicians and Surgeons of Canada, and Society for Experimental Biology and Medicine
Disclosure: Secretory IgA, Inc. Ownership interest Management position

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva Consulting; Meda Honoraria Speaking and teaching

Further Reading