Immunoglobulin M Deficiency
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Selective immunoglobulin M (SIgM) deficiency is a rare form of dysgammaglobulinemia characterized by an isolated low level of serum immunoglobulin M (IgM). [1] Reported IgM concentrations in SIgM deficiency vary from 40 mg/dL (though some sources say 20 mg/dL) to undetectable levels (reference range 45-150 mg/dL in adults). [2] Recent series report IgM levels of 29.7±8.7 mg/dL (mean±SD) for adults and 16.5±13.8 (mean±SD) in children. [3, 4] In this context, remember that 2.1% of “normal” individuals have values < 2 SD below the mean and that values in children must be compared with reference range values for age. [5] The levels of other immunoglobulin classes are within reference ranges.
SIgM deficiency may occur as a primary or secondary condition. [6] Secondary SIgM deficiency is much more common than primary SIgM deficiency and may be seen in association with malignancy, autoimmune disease, gastrointestinal disease, and immunosuppressive treatment. [1]
Some patients are asymptomatic, whereas others (often infants and small children) develop serious infections. Patients may develop prolonged or life-threatening infections caused by both encapsulated bacteria and viruses, especially in infancy. In older children and adults, SIgM deficiency is usually discovered during the investigation of other conditions, such as autoimmune disease or malignancy. [1]
Serum immunoglobulin levels are controlled by intricate immunological regulatory mechanisms, and heterogeneity is believed to exist in the pathogenesis of SIgM deficiency. Little is known about the pathological features of SIgM deficiency at a cellular level, given that the condition is so uncommon. Processes that control the survival of IgM in the circulation and may otherwise regulate its concentration in serum have not been well described; alterations in clearance mechanisms, in addition to altered production of IgM by lymphocytes, may contribute to selective deficiency of this immunoglobulin isotype.
The cause of SIgM deficiency is unknown. Increased regulatory T-cell activity specific for IgM has been described. [7] The absence of IgM in the presence of normal levels of immunoglobulin G (IgG) and immunoglobulin A (IgA) has yet to be explained, as this appears to contradict the theory of sequential immunoglobulin gene rearrangement. Normal mature B cells are expected to have IgM and immunoglobulin D (IgD) on their surfaces, and, with proper stimulation, rearrange their immunoglobulin genes to switch from expressing IgM to IgG, IgA, or immunoglobulin E (IgE).
Having normal levels of IgG and IgA in the face of low IgM is thus counterintuitive. One could speculate that failure to regenerate B-cell precursors could lead first to depletion of IgM, with gradual loss of IgG and other isotypes occurring later as class-switched memory B-cells and plasma cells fail to be replaced. This hypothesis has not been tested, and few studies are available to determine whether only the serum IgM level is low or whether the number of B cells with surface IgM is also decreased in patients with selective IgM deficiency. Gradually, current state-of-the-art laboratory technology is being applied in studying patients with SIgM deficiency, though much remains to be learned.
The currently available literature suggests a heterogeneous population of patients of SIgM deficiency. Some patients are capable of normal antibody responses of other immunoglobulin classes following specific immunization, whereas others respond poorly. Certain patients with decreased helper T-cell activity have been described. [8] Cell-mediated immunity appears to be intact, but an insufficient number of detailed studies are available to confirm this. Suggested etiologies include rapid isotype switching of B cells from production of IgM to production of other isotypes and hypercatabolism of IgM.
United States
In a retrospective study of a large allergy practice (20,000 patients) database, Goldstein et al reported prevalences of SIgM deficiency of 0.26% among adults and 0.03% among children. [3, 4]
International
SIgM deficiency is rare, with an incidence of less than 0.03% in the general population and 1% in hospitalized patients. [9]
Since IgM may have a different range of specificities than placentally-transferred maternal IgG, infants can succumb to overwhelming infections such as meningitis, pneumonia, and gram-negative sepsis.
Patients with SIgM deficiency are susceptible to recurrent sepsis and overwhelming infection with encapsulated bacteria (eg, Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae). [10, 11, 12] They may also have autoimmune disease including glomerulonephritis and osteomyelitis from which organisms are not recoverable, [13, 14, 15] as well as malignancies, chronic dermatitis, diarrhea, and upper respiratory infections.
The incidence of SIgM deficiency in various races has not been reported, given the low overall incidence.
The disorder occurs in both males and females, with no known discrepancies between the sexes.
Infants can present with severe and overwhelming infections. Older children may present with recurrent sinopulmonary infections secondary to encapsulated organisms and an increased incidence of gram-negative septicemia.
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Ideura G, Agematsu K, Komatsu Y, Hatayama O, Yasuo M, Tsushima K, et al. Selective IgM Deficiency Accompanied with IgG4 Deficiency, Dermal Complications and a Bronchial Polyp. Allergol Int. Mar 2008. 57(1):99-105. [Medline].
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Makay B, Unsal E, Anal O, Gunes D, Men S, Cakmakci H, et al. Chronic recurrent multifocal osteomyelitis in a patient with selective immunoglobulin M deficiency. Rheumatol Int. 2009 May. 29(7):811-815. [Medline].
Jung CL, Cha MK, Jun BH, Hong KS. A case of IgM deficiency with B cell deficiency detected by ABO discrepancy in a patient with acute osteomyelitis. Ann Lab Med. 2013 May. 33(3):208-11. [Medline]. [Full Text].
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Gul U, Soylu S, Yavuzer R. Epidermodysplasia verruciformis associated with isolated IgM deficiency. Indian J Dermatol Venereol Leprol. 2007 Nov-Dec. 73(6):420-2. [Medline].
Zaka-ur-Rab Z, Gupta P. Pseudomonas septicemia in selective IgM deficiency. Indian Pediatrics. 2005. 42:961-2.
Stagi S, Azzari C, Bindi G, et al. Undetectable serum IgA and low IgM concentration in children with congenital hypothyroidism. Clin Immunol. 2005. 116:94-8.
Lim SH, Zhang Y, Wang Z, et al. Rituximab administration following autologous stem cell transplantation for multiple myeloma is associated with severe IgM deficiency. Blood. 2004. 103:1971-2.
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Ideura G, Agematsu K, Komatsu Y, et al. Selective IgM deficiency accompanied with IgG4 deficiency, dermal complications and a bronchial polyp. Allergol Int. 2008 Mar. 57(1):99-105. [Medline].
Nies KM, Stevens RH, Louie JS. Impaired immunoglobulin M synthesis by peripheral blood lymphocytes in systemic lupus erythematosus: a primary B-cell defect. Clin Immunol Immunopathol. 1981 Apr. 19(1):118-30. [Medline].
Iftikhar Hussain, MD Director of Allergy, Asthma, and Immunology Center, PC
Iftikhar Hussain, MD 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 Thoracic Society, Association of Clinical Research Professionals
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Srividya Sridhara, MD Resident Physician, Department of Internal Medicine, University of Oklahoma
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Bilal Ahmed, MD
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Jessica P Bhoyroo, MSc Research Associate
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Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Michael R Simon, MD, MA Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Oakland University William Beaumont 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, Society for Experimental Biology and Medicine
Disclosure: Have a 5% or greater equity interest in: Secretory IgA, Inc. ; siRNAx, Inc.<br/>Received income in an amount equal to or greater than $250 from: siRNAx, Inc.
Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; 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, Association of American Physicians
Disclosure: Nothing to disclose.
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, Clinical Immunology Society
Disclosure: Received salary from CSL Behring for employment; Received ownership interest from CSL Behring for employment; Received consulting fee from America”s Health insurance plans for subject matter expert for clinical immunization safety assessment network acvtivity of cdc.
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author Christina O’Relley Barnes, MD, to the development and writing of this article.
Immunoglobulin M Deficiency
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