Special Series: Practical Diagnosis and Management of Immunodeficiency

Patients with abnormal IgM levels: assessment,

clinical interpretation, and treatment
Hans D. Ochs, MD
INTRODUCTION
This review of the role of IgM in cognate immunity is part of
a series on ambulatory diagnoses and management of primary
immune deficiency diseases edited by Chitra Dinakar, University of Missouri.1 IgM is phylogenetically the earliest
antibody class identified and the first immunoglobulin isotype to appear in the circulation after exposure to a new
antigen. IgM plays an important role in the ontogeny of B
cells and in early cognate immune responses.2 VDJ rearrangement of the immunoglobulin heavy chain occurs at the pre
B-cell stage, when light chains are still of the surrogate type
(5/VpreB). Further maturation leads to immature B cells,
which express surface IgM and IgD and carry and light
chains, creating a functional B-cell receptor that allows antigen recognition and further development into unswitched
memory B cells (IgM/D, CD27). After interaction with
the T-cell receptor of antigen-specific CD4 T cells via major
histocompatibility complex II and costimulatory molecules
(CD40 ligand [CD40L]/CD40, inducible costimulator
[ICOS]/ICOS ligand), mature B cells undergo isotype switching, resulting in B cells expressing CD27 and IgG, IgA, or
IgE. Whereas IgM is responsible for rapid and early generation of antibody, long-term humoral immunity is initiated by
the production of high-affinity IgG or IgA antibody. The
demonstration of IgM antibodies to a specific infectious agent
can be used as an indicator of recent infection. The presence
of IgM in cord blood (20 mg/dL) may indicate prenatal
infection because IgM antibody cannot be acquired from the
mother by transplacental passage. In infants, IgM serum
levels increase rapidly from a mean of 11 mg/dL at term to 55
mg/dL at 1 year of age. By 2 years, IgM concentration is
approximately 60% of that in adults.
IgM is expressed as a monomer on the surface of nave and
mature unswitched B cells, where it forms the antigen receptor complex together with the coreceptors Ig and Ig. If
secreted, most IgM forms a pentameric complex, which stays

Affiliations: Department of Pediatrics, University of Washington School

of Medicine, Childrens Hospital and Regional Medical Center, Seattle
Childrens Hospital Research Institute, Seattle, Washington.
Disclosures: Author has nothing to disclose.
Funding Sources: Funded by an unrestricted educational grant from
Talecris Biotherapeutics.
Received for publication December 20, 2007; Received in revised form
February 20, 2008; Accepted for publication February 28, 2008.

VOLUME 100, MAY, 2008

mostly (70% to 80%) intravascular. Its half-life is approximately 6 days, in contrast to IgG, which has a half-life of 21
to 28 days. IgM antibodies are uniquely efficient in agglutination and are highly avid because of their multimeric nature
and strong complement fixation.
IgM LEVELS AND DISEASE
Because of the central role of IgM in the development of B
cells and because class switch recombination (CSR) and
somatic hypermutation (SH) require sophisticated intrinsic
and extrinsic mechanisms, evaluation of serum IgM levels
provides an informative insight into primary and secondary
immunodeficiency disorders. Quantitation of serum immunoglobulin is generally performed by nephelometry that detects
IgM at concentrations as low as 6 mg/dL. IgM is age dependent during childhood but otherwise stable over time. If
abnormal, IgM levels, like all tests, should be rechecked to
avoid laboratory errors. Loss of serum proteins can occur
through the gut, in the kidneys, or by excessive drainage from
the thoracic or peritoneal cavities and may lead to hypogammaglobulinemia, affecting low-molecular-weight immunoglobulins (eg, IgG and IgA) more than IgM, which is
secreted as a 900,000-molecular-weight protein. Since the
pentameric structure of IgM favors agglutination, quantitation of isohemagglutinin titers is an excellent test for functional IgM. Low serum IgM levels in the context of hypogammaglobulinemia may indicate molecular defects that
disrupt cell signaling or gene expression directly, thus interfering with B- and T-cell development. On the other hand,
mutations of genes required for CSR and SH result frequently
in increased serum IgM levels.
SELECTIVE IgM DEFICIENCY
Isolated absence or reduction of serum IgM in view of otherwise normal immunoglobulin isotypes and T-cell function
is known as selective IgM deficiency. Some patients with
selective IgM deficiency are asymptomatic. Selective IgM
deficiency has been defined as IgM levels of less than 2 SDs
or less than 10% of the mean for age (eg, 5 to 15 mg/dL in
infants and children and 20 mg/dL in adults). Considering
the importance of IgM in the ontogeny of B-cell development, the selective absence of IgM in the presence of normal
numbers of circulating B cells is difficult to explain. In vitro
studies have identified defective B-cell function35 or the

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