Introduction

IgM immunoglobulins are produced by plasma cells as part of the body's adaptive humoral immune response against a foreign pathogen. Resting mature yet naive, B lymphocytes express IgM as a transmembrane antigen receptor that functions as part of the B-cell receptor (BCR). B cell activation in response to antigen binding to the BCR results in rapid cell division and clonal expansion of the activated B lymphocyte, producing many progeny cells that can differentiate into either antibody-secreting plasma cells or memory B lymphocytes. Antibodies are similar in structure to transmembrane immunoglobulins yet lack a short transmembrane segment at the carboxy-terminal end. IgM is the first antibody secreted by the adaptive immune system in response to a foreign antigen. Monomeric IgM is a heterotetramer of approximately 180 kDa. However, the secreted form of IgM exists predominantly in a pentameric configuration with a molecular weight greater than 900 kDa. In serum, the IgM has a half-life of approximately 5 to 10 days and is composed of approximately 12% carbohydrates by weight.[1] The average serum concentration of IgM in the body is about 1.5 mg/ml.  

Fundamentals

Immunoglobulins are heterotetramers comprised of two heavy chains and two light chains linked together by covalent bonds. Immunoglobulins are Y-shaped molecules containing two Fab regions that recognize antigen and an Fc tailpiece that determine the biological activity of the antibody. In humans, the heavy chain locus is on chromosome 14, and two alternative light chain loci, known as kappa and lambda, are located on chromosomes 2 and 22, respectively. Immunoglobulins, or antibodies in the secreted form, are produced by somatic DNA recombination in B lymphocytes developing in the bone marrow, the primary lymphoid organ for B lymphocyte development. Somatic recombination is a strategy used by the adaptive immune system to generate trillions of different immunoglobulins and T-cell receptors by recombining different protein-encoding DNA segments together in a fairly random manner. Monomeric IgM and IgD serve as the BCRs for resting B lymphocytes that have not been stimulated by antigen recognition. 

Upon recognizing antigen, pentameric IgM is the initial antibody secreted by B cells in response to an antigen challenge. The IgM secreted in a primary response tends to have a lower affinity for foreign antigen compared to isotypes secreted on subsequent encounters, or secondary responses, to a foreign antigen. However, due to its pentameric conformation, secreted IgM has higher avidity, or overall strength of binding to antigen, due to the presence of ten antigen-binding sites per pentameric IgM molecule. The increased avidity of IgM is important for binding pathogens with repetitive epitopes, such as on a bacterial capsule. IgM is present predominantly in the blood, although it can also appear in the lymph and can also be secreted across mucosal surfaces. Unlike IgG or IgE, multimeric IgM does not readily enter the tissues from the bloodstream due to its larger size. J chain is a small 15 kDa protein that is associated with secreted pentameric IgM and dimeric IgA. Pentameric IgM is stabilized by covalent, disulfide bonds between the Fc regions of IgM molecules, as well as disulfide bonds between the J chain and the Fc regions of IgM. Hexameric IgM in humans is less well characterized than pentameric IgM, and hexameric IgM assembles independently of the J chain. The presence of the J chain protects secreted IgM and IgA from proteases and also facilitates their transport across mucosal epithelia to provide immune protection to mucosal surfaces. 

Cellular Level

The bone marrow is the primary lymphoid organ for B cell development after birth, and the production of new B cells occurs throughout the life of a healthy individual. Developing B cells that can successfully produce a transmembrane IgM BCR that is non-reactive to self are permitted to leave the bone marrow as immature B cells expressing transmembrane IgM. Immature B cells migrate to the spleen, where they must compete with other B cells to access follicles within the spleen to receive survival signals. Only a portion of immature B cells entering the spleen survive to become mature, yet naive, B cells, and these bone-marrow-derived B cells are B-2 cells. Mature B-2 cells have two fates, as they can differentiate into either follicular B cells or marginal zone B cells; the majority of B cells in the human body are follicular B cells. Follicular B cells leave the spleen expressing both IgM and IgD as transmembrane BCRs and begin migrating through secondary lymphoid organs such as lymph nodes, mucosal tissues, and spleen in search of antigen. Follicular B cells predominantly recognize peptide antigens and are thymus-dependent, as they require help from T lymphocytes to become fully activated against a foreign antigen. With the assistance of T-cells, follicular B cells undergo clonal expansion in response to foreign antigen recognition, producing progeny that can differentiate into either antibody-producing plasma cells or memory B lymphocytes. IgM is the primary antibody produced during an initial antigen challenge. Yet, upon subsequent antigen exposure, follicular B cells undergo isotype switching, resulting in IgG, IgG, IgE, or IgA production. Furthermore, T-dependent B cells undergo somatic hypermutation and affinity maturation on repeat antigen exposure, resulting in the production of antibodies such as IgG with increased affinity for the foreign antigen.

Marginal zone B cells are also bone marrow-derived B-2 cells that complete their maturation in the spleen and largely remain in the spleen, localizing in the marginal zone between the red and white pulp junctions, where they provide the first line of defense against blood-borne pathogens.[2] Marginal zone B lymphocytes are predominantly thymus-independent and primarily recognize non-peptide antigens such as polysaccharides and lipids. Since they can become activated in the absence of help from T cells, marginal zone B cells largely produce IgM and do not undergo isotype switching, affinity maturation, or memory lymphocyte formation upon repeat exposure to an antigen. Marginal zone B cells contribute to the production of natural antibodies. Natural antibodies are predominantly IgM antibodies produced in the absence of exposure to a foreign antigen; these antibodies are cross-reactive against polysaccharide and lipid antigens commonly found in microorganisms. Researchers observe natural antibodies in laboratory mice raised in the absence of microbes. Therefore, it appears that endogenous signals induce natural antibody production, and these antibodies can be considered part of the innate immune system.[3] Importantly, marginal zone B cells appear to contribute to IgM production directed against encapsulated bacteria, and antibody fixation of encapsulated bacterium such as Streptococcus pneumoniae or Haemophilus influenzae is extremely important for their eradication.

B-1 cells represent a third subset of B cells derived from the fetal liver, rather than the bone marrow, and exhibit a limited diversity of antibody production, which is predominantly IgM. B-1 cells are self-renewing and primarily found at mucosal layers and the peritoneal cavity, representing an additional source of thymus-independent natural antibodies. Similar to marginal zone B cells, B-1 cells produce primarily IgM of limited diversity against polysaccharides and lipids commonly found in microbial species. They do not undergo isotype switching, affinity maturation, or memory lymphocyte formation upon subsequent antigen exposure.[4]

Molecular Level

Immunoglobulins are heterotetramers comprised of two heavy and two light chains, each composed of both variable and constant domains. The variable regions of immunoglobulins determine antigen-binding specificity, whereas the constant region of the heavy chain determines cellular function. The heavy chain locus on chromosome 14 contains approximately 45 variable (V) encoding regions, 23 diversity (D) regions, and six joining (J) regions. Please note that the J encoding regions of DNA in the heavy chain locus are distinct and not related to the J chain peptide associated with pentameric IgM secretion. Maturing B lymphocytes and T lymphocytes both arise from CD34-positive hematopoietic stem cells in the bone marrow. Expression of the RAG1 (recombination-activating gene) and RAG2 genes is unique to developing B and T lymphocytes, and the proteins produced by these genes form the RAG complex (alternatively referred to as the VDJ recombinase), which catalyzes somatic recombination between V, D, and J segments in a somewhat random manner. CD19-positive pro-B cells in the bone marrow express the RAG complex to initiate recombination between segments on the heavy chain locus, initially between D and J segments, and subsequently between V and D segments. Combinatorial diversity refers to the tremendous diversity of immunoglobulins generated from the same genetic locus through random recombination events between V, D, and J coding segments. Junctional diversity is an additional process utilized to increase the diverse repertoire of immunoglobulins made from the same relatively small genetic locus. It is associated with the random incorporation of nucleotides at the junctions between the V, D, and J segments. For example, expression of the enzyme TdT (Terminal deoxynucleotidyl transferase) results in the random addition of nucleotides (N nucleotides) between the exon-encoding V, D, and J segments. Many of these nucleotide additions will not produce a functional heavy chain due to shifts in the reading frame introduced by incorporating N nucleotides, such as developing B lymphocytes unable to make a functional heavy chain die through apoptosis. The BCR receptor checkpoint refers to the requirement for developing B cells to successfully produce a heavy chain that can make it to the cell surface while associated with a germline-encoded surrogate light chain, forming the pre-BCR receptor. Cells that successfully form a pre-B cell receptor are referred to as large pre-B cells, and the pre-B cell receptor transmits pro-survival and proliferative signals to promote the continued development of the large pre-B cell. Bruton's tyrosine kinase (BTK) is a kinase required in this signal transduction pathway, and patients lacking a functional BTK protein suffer from X-linked agammaglobulinemia, as developing B cells do not pass this checkpoint. Pre-B cells inhibit further attempts to recombine the heavy chain locus, ensuring that one heavy chain is made per individual B cell, and RAG-mediated recombination of the light chain loci commences. Both light chain loci, the kappa and lambda loci, have approximately 30 V segments and 5 J segments that can be differentially recombined. Unlike the heavy chain loci, the light chain loci do not contain D segments. Light chain recombination in pre-B cells predominantly occurs initially on the kappa loci, and if a pre-B cell is unable to form an IgM immunoglobulin that is non-reactive to self-antigens in the bone marrow using the two kappa loci, recombination of the lambda loci initiates. If a functional light chain is produced, resulting in a non-self reacting IgM molecule at the surface, the recombination of other light chain loci becomes inhibited. This process, referred to as allelic exclusion, ensures that circulating B-2 lymphocytes produce immunoglobulins with a distinct antigen recognition site. Since the kappa light chains are attempted first in the recombination process, this explains why the majority of antibodies, including IgM, contain kappa light chains. Circulating mature, yet naive, follicular B cells express both IgM and IgD as transmembrane antigen receptors. The mu and delta genes for the heavy chains of IgM and IgD, respectively, are located proximal to the VDJ encoding regions of the heavy chain locus, and alternate RNA processing of the primary RNA transcript produces both transmembrane IgM and IgD on naive B cells. A transmembrane immunoglobulin is not capable of transmitting intracellular signals to the B cell in response to antigen binding, and therefore transmembrane immunoglobulins associate with Ig alpha and Ig beta proteins to form the BCR. The Ig alpha and Ig beta proteins contain the immunoreceptor tyrosine-based activation (ITAM) motifs required to stimulate naive B cell activation in response to transmembrane IgM or IgD recognition of antigen. Initial naive B cell activation in response to antigen recognition results in IgM antibody secretion. Alternative polyadenylation site selection of the primary transcript results in substitution of a short hydrophilic sequence for a transmembrane domain at the carboxy terminus, resulting in IgM secretion. Due to cysteine residues in this hydrophilic sequence at the carboxy terminus, IgM oligomerizes during the secretory pathway to form pentameric IgM connected by a J chain, or alternatively, as a hexamer without the J chain.[5] A single IgM molecule is similar to IgE in that it contains four constant heavy domains and lacks a hinge region. Therefore, IgM molecules have slightly less flexibility and freedom of rotation compared to IgG, IgA, or IgD molecules.

Function

IgM antibodies secreted by B cells participate in both neutralization and clearance of pathogens in addition to initiating inflammatory reactions against pathogens through the complement pathway. IgM is the predominant antibody during a primary challenge to an antigen, and for some non-peptide antigens, IgM may be the only isotype of antibody secreted on subsequent encounters with the antigen. The primary humoral immune response to a novel pathogen typically requires close to a week before substantial amounts of IgM appear in the blood, and the innate immune response is necessary to fight the infection until the creation of T cells and antibody-secreting plasma cells clonally expanded against the pathogen in sufficient numbers. Neutralization refers to the ability of antibodies to protect against infection by binding pathogen antigens critical for adherence to host tissues. The ability of antibodies to neutralize pathogens is a major protective benefit of vaccines, as it prevents pathogens from initiating infection by binding to host cells. IgM can neutralize pathogens, though not as effectively as IgG or IgA isotypes, most likely due to the increased flexibility of these isotypes provided by a hinge region. 

IgM predominantly serves as a potent activator of the classical complement pathway in the circulatory system.[6] The C1 complex is required to activate the classical pathway of complement and is composed of the hexameric C1q protein bound to a tetramer of proteases, two molecules of C1r, and two molecules of C1s. Both IgG and IgM can activate the classical pathway of complement through binding of C1q to the Fc portions of IgG and IgM. However, a single pentameric IgM molecule bound to a pathogen is sufficient to activate C1q, whereas two independent IgG molecules are required to recognize a pathogen to activate C1q. C1q must bind to two Fc regions of immunoglobulins to become activated. In contrast to IgG molecules that contain one Fc domain, pentameric IgM has five different Fc domains on the same molecule, facilitating rapid complement activation when a single IgM molecule recognizes a pathogen. C1q does not bind to soluble IgM as the conformation of unbound IgM masks the Fc portions of the molecule from C1q. Recognition of bound antibodies by C1q results in activation of the C1r and C1s proteases of the C1 complex, which subsequently cleave C4 and C2, resulting in the deposition of C4b2a C3 convertase on the pathogen surface. The formation of a C3 convertase on the pathogen surface results in cleavage of C3, producing C3a and C3b, and the subsequent steps of complement activation are fairly similar between the classical, alternative, and lectin pathways of complement. C3a functions as an anaphylatoxin and recruits inflammatory cells such as neutrophils to the site of the infection. C3b is a powerful opsonin, and the deposition of C3b on a pathogen in the blood by IgM activation of the complement system results in clearance of the pathogen by macrophages in the spleen and the liver. Finally, activation of complement can also result in the formation of a C5 convertase, and binding of C5 on the pathogen surface results in the recruitment of C5, C6, C7, C8, and C9 molecules on the pathogen surface, promoting the formation of the membrane attack complex (MAC). The MAC forms a hole on the pathogen's surface, resulting in loss of osmotic control leading to death by cell lysis. Neisseria sp. and erythrocytes, in particular, are susceptible to death by MAC-mediated lysis. By serving as a potent activator of complement, IgM serves as a powerful activator of complement and helps activate inflammation, opsonization, and destruction of pathogens that have gained access to the circulatory system. IgM is especially important for eradicating encapsulated bacteria, such as S. pneumoniae, H. influenzae, Neisseria meningitidis, Klebsiella pneumoniae, and Pseudomonas aeruginosa. 

Due to its large size, IgM cannot readily leave the circulatory system and enter tissues compared with IgG, IgE, and monomeric IgA. Although IgM is predominantly associated with the protection of the vasculature, IgM also has the ability to protect mucosal surfaces, although not normally to as great an extent as IgA. Both pentameric IgM and dimeric IgA can be transported across mucosal epithelial layers through the polymeric immunoglobulin receptor (poly-Ig receptor). The poly-Ig receptor is located on the basolateral surface of mucosal epithelial layers and binds to either pentameric IgM or dimeric IgA through interaction with the J chain, resulting in transcytosis across the mucosal epithelial layer and release of the antibody from the apical surface. IgA is the predominant antibody used to protect mucosal surfaces such as the gut or lungs. Yet, mucosal IgM secretion also occurs and can be dramatically upregulated if IgA secretion is insufficient, which explains why many individuals with selective IgA deficiency do not suffer severe deleterious effects due to the increased secretion of other isotypes across mucosal surfaces such as IgM. The primary mechanism of antibody protection in the lumen of the gut or lungs is neutralization. Finally, IgM can serve as an opsonin, albeit not as powerful an opsonin as C3b, IgG1, or IgG3, and IgM appears to possess additional properties. IgM appears to facilitate the clearance of apoptotic cells and serve other immunomodulatory properties through two additional receptors for IgM, the FcμR (FCMR) receptor specific for IgM (FCMR), and an Fc receptor that recognizes both IgM and IgA, Fcα/μR.[7]

Testing

The detection of IgM or IgG in an individual can demonstrate that the person has suffered exposure to a pathogen. Yet the detection of IgM or IgG antibodies against a pathogen can not indicate whether a person is still harboring the specific pathogen or whether the body has been able to successfully eliminate the pathogen, as long-lived plasma cells are a component of immunological memory that can produce antibodies against an offending pathogen long after successful clearance of the pathogen. In some cases, such as with Lyme disease, a patient may seek medical attention due to symptoms in the first days of the infection before the ability of the humoral immune system to produce IgM as part of the primary immune response to a pathogen. Furthermore, the absence of IgM or IgG antibodies directed against a pathogen can be problematic to interpret if the individual is suffering from a congenital or acquired immunodeficiency. The detection of IgM to determine exposure to a pathogen is especially useful for neonates. If pregnant women suffer exposure to a pathogen, it is crucial to determine whether the newborn child has also had exposure. Detection of IgG in the neonate is not as useful for this purpose, as IgG is readily transferred across the placenta to protect the fetus against pathogens the pregnant mother has been exposed to previously. The IgG passively transferred to a newborn will gradually breakdown over the first six months of life. IgM is the first immunoglobulin produced in the neonate. Therefore, the detection of IgM raised against a pathogen in a neonate indicates exposure to the pathogen by the neonate.[8]Due to its larger conformation, pentameric IgM can efficiently agglutinate erythrocytes or cause red blood cell clumping, a process referred to as hemagglutination. IgM antibodies directed against the glycolipid antigens associated with the ABO blood group are an extremely important consideration for blood transfusions, as a type O individual, for example, that received type A or B blood will suffer intravascular hemolysis due to activation of IgM-mediated complement on the donor erythrocytes, resulting in shock and disseminated intravascular coagulation. The hemoglobin released from lysed erythrocytes is toxic to the kidney, and acute renal failure and possibly death can result if the wrong blood type is administered. Agglutinins such as anti-A or anti-B blood group antibodies bind Group A and B glycolipid antigens respectively and cause agglutination; this property is useful in determining the ABO blood type of an individual. Before a blood transfusion, a patient's serum is incubated with prospective donor blood cells as a final screen to detect for agglutination, which can detect whether the blood and recipient are incompatible. Finally, since the ABO antigens are highly expressed on vascularized tissue such as the kidney, screening for harmful incompatible IgM antibodies directed against blood group antigens is performed before kidney transplants to prevent hyperacute rejections of the transplanted kidneys.

Clinical Significance

IgM is the initial antibody produced by the adaptive immune system in response to a foreign pathogen. IgM is also the primary constituent of natural antibodies that represent a branch of the innate immune system.  There are many disorders associated with IgM; a description of some of the most pertinent disorders appears below: 

X-linked Hyper-IgM Syndrome

Hyper-IgM syndrome is predominantly a rare X-linked inherited disease that occurs in approximately 2 out of 1,000,000 million males.[9] The disease characteristically demonstrates elevated IgM levels, deficient levels of other immunoglobulins, and defects in cellular immunity. Isotype switching is a feature of secondary responses to a pathogen by the humoral immune system, resulting in the production of IgG, IgA, or IgE antibodies directed against the pathogen. The isotype class chosen upon subsequent antigen exposure is largely a function of the cytokines secreted by T helper cells. The vast majority of isotype switching events require interaction between CD40 ligand (CD40L) on activated T cells with CD40 on B cells. Defective interactions between CD40L and CD40 result in defects in isotype switching, affinity maturation, and memory lymphocyte formation in B cells. T-cell activation of macrophages and dendritic cells also requires CD40L-CD40 interactions, and therefore these cell types are also adversely affected. Patients with hyper-IgM syndrome exhibit elevated levels of IgM, the normal IgM in the serum of adults is between 37-286 mg/dl, while IgA, IgG, or IgE levels may be lower than normal or undetectable.[10] Although IgM levels are typically elevated, IgM directed against peptide antigens is often compromised, as CD40L-CD40 productive interactions are necessary to activate most B-2 follicular B cells. Therefore, one would expect the levels of anti-A and anti-B IgM antibodies in a type O patient with hyper-IgM syndrome to be elevated, yet the patient would be expected to have an inadequate immune response against peptide antigens such as the tetanus toxoid vaccine. Additionally, germinal centers are not observed in the lymph nodes of individuals with X-linked hyper-IgM syndrome, as the creation of germinal centers also requires specific interactions between B cells and T-helper cells. Since the gene for CD40L is on the X-chromosome, it is the most common genetic defect affecting isotype switching, although autosomal recessive defects in other genes such as CD40, NEMO, AID, or UNG can also result in hyper-IgM syndrome, albeit much more rarely.[11] Because CD40L-CD40 interactions are also necessary for productive interactions between activated T cells and macrophages, cellular immunity is also adversely affected, and cytokines secreted by macrophages to stimulate neutrophil production are often present at insufficient levels.

Individuals with X-linked hyper-IgM syndrome are susceptible to recurrent sinopulmonary and pyogenic infections (e.g., H. influenzae, S. pyogenes) due to their inability to form IgG that can enter tissues from the blood to fight extracellular bacteria. Since cellular immunity is also compromised, defects in CD40L-CD40 signaling result in combined immunodeficiency. The inability to activate macrophages results in a significantly increased susceptibility to the opportunistic fungal pathogen Pneumocystis jirovecii, and pneumonia caused by P. jirovecii in a child often is the symptom of the disease. Diarrhea occurs in approximately one-third of patients due to infections by parasites such as Cryptosporidium parvum. Uncontrolled cytomegalovirus infection may lead to liver disease, and individuals with CD40L deficiencies are also at a greater risk for developing malignancies, presumably due to defective cellular immunity. Individuals with hyper-IgM syndrome caused by mutations in loci other than CD40L or CD40 will only experience humoral defects and will not experience compromised cellular immunity. 

The initial diagnosis of X-linked hyper-IgM syndrome is made predominantly on the clinical symptoms of a patient with an uncontrolled infection that exhibits normal or elevated IgM levels, with very low or undetectable IgG and IgA levels. Flow cytometry can be conducted for the presence of CD40L on T-cells activated in vitro, although identification of the relevant mutation (e.g., CD40L in a male patient) by genetic testing is useful for definitive analysis. Patients with hyper-IgM syndromes r administered intravenous gammaglobulin (IVIG) regardless of the genetic cause of the disease. X-linked hyper-IgM patients also receive trimethoprim-cotrimoxazole as a prophylactic treatment against P. jirovecii infection. Protective measures against exposure to Cryptosporidium sp. are also advised, for example, by avoiding swimming in lakes to avoid exposure to C. parvum cysts, as an active C. parvum infection is challenging to treat. GM-CSF can be administered to patients to treat sores and blisters that result from neutropenia caused by defective macrophage activation.  

Selective IgM Deficiency

Selective IgM deficiency (SIGMD) is a rare disorder with fewer than 300 cases reported. SIGMD is associated with an isolated deficiency in IgM in the presence of normal levels of other immunoglobulins such as IgG and IgA and normal levels of T cells and other leukocytes.[12] Individuals with SIGMD may be asymptomatic, or they may suffer from recurring infections from encapsulated bacteria (e.g., S. pneumoniae and H. influenzae) in addition to viral infections. Additionally, SIGMD can be associated with malignancy, autoimmunity, or allergy. SIGMD may occur as a secondary effect of another disease, such as malignancy or bacteremia. Yet, primary causes of SIGMD have also been described, as some are associated with deletions on chromosome 22, for example.[12] The diagnosis of SIGMD is one of exclusion. Other diseases that result in low levels of multiple isotypes must be excluded, such as common variable immunodeficiency or X-linked agammaglobulinemia, which will likely result in reduced levels of several antibody isotypes. Conversely, Wiskott-Aldrich syndrome is often associated with low IgM yet elevated levels of IgG and IgA. Cold Agglutinin Disease 

Cold agglutinin disease (CAD) is a form of autoimmune hemolytic anemia (AHA) mediated predominantly by IgM antibodies. As the name of the disease implies, IgM recognizing these erythrocyte antigens can agglutinate erythrocytes at colder temperatures. IgG or IgM antibodies that bind to erythrocytes can lead to red blood cell destruction by either promoting opsonization and clearance of erythrocytes by phagocytes in the spleen or liver or by activating complement leading to erythrocyte lysis as a result of MAC formation. Autoantibodies can cause AHA, can be induced by an infection, or can be drug-induced, in which case antibodies recognize complexes of drugs bound to erythrocytes. CAD is a rare disease affecting approximately 16 per million and is predominantly associated with IgM autoantibodies directed against the blood group antigens large I and small i.[13][14] These ubiquitously expressed antigens are polysaccharides, and due to their relatively weak non-covalent interactions with IgM, IgM binding to the antigens is significantly strengthed at lower temperatures when erythrocytes circulate in the periphery. Binding of IgM to erythrocytes activates the classical complement pathway, resulting in attachment of the opsonin C3b to the erythrocyte. This IgM-mediated C3b binding to the erythrocyte is stable even when the erythrocyte returns closer to core body temperatures, resulting in dissociation of IgM. Therefore, CAD can promote hemolytic destruction of erythrocytes through opsonization by macrophages in the spleen or liver. In contrast, autoantibodies that bind to erythrocytes at warmer temperatures are typically IgG. These temperature-dependent differences in antibody binding between IgM and IgG appear to reflect the thermodynamic differences between polysaccharide and peptide binding, respectively, as recognition of peptide antigens can involve hydrophobic interactions, which are relatively strong non-covalent forces not found in interactions between polysaccharides. CAD is a relapsing disease in which the severity of disease fluctuates depending on the concentration of antibodies and how well they can activate complement. CAD may occur as a result of an underlying condition such as a result of an infection or undiagnosed lymphoproliferative disorder. CAD is often associated with infections by either the Epstein-Barr virus, the cause of infectious mononucleosis, or M. pneumoniae, the primary cause of atypical pneumonia.  For patients that suffer debilitating symptoms due to CAD, avoidance of cold temperatures is paramount, including drinking cold liquids or being in cold rooms. Severe anemia can be treated with transfusions and plasmapheresis to remove the IgM molecules serving as cold agglutinins. It bears mentioning that all intravenous solutions should be warmed to body temperature yet must not exceed 40 degrees centigrade before infusion. Patients with CAD should undergo evaluation for an underlying disorder; antimicrobial therapy, for example, is warranted if an infection is associated with the condition. CAD may also occur from other primary causes such as non-Hodgkin lymphoma, and therefore flow cytometry of leukocytes biopsied from the bone marrow is useful in this regard. Rituximab is very useful for the treatment of debilitating CAD that is not associated with a malignancy, and the ability to treat CAD with inhibitors of complement is an area of active investigation. Monoclonal Gammopathies

Monoclonal gammopathies are characterized by the proliferation of single clones of plasma cells. Several monoclonal gammopathies are associated with the overproduction of IgM, a condition that can be referred to as macroglobulinemia, as the letter designation of IgM derived from its original description as macroglobulin, due to its much larger size in comparison to IgG. Waldenström macroglobulinemia (WM) is a rare example of such a disorder that most commonly presents in the seventh decade of life. In addition to elevated serum IgM, WM results in the infiltration of the bone marrow by a lymphoplasmacytic lymphoma, a low-grade and slow-growing form of non-Hodgkin's lymphoma. Patients with WM most commonly present with a pale appearance, oronasal bleeding, organomegaly, and other systemic complaints such as weakness and fatigue. The absence of involvement of the bone or kidneys is useful in distinguishing WM from multiple myeloma. An increased hyperviscosity of the blood due to increased IgM secretion can lead to CNS effects, such as headache, loss of vision, ataxia, weakness, deafness, and dilated retinal veins. Such symptoms associated with WM hyperviscosity are a potential medical emergency and should receive treatment with plasmapheresis. The criteria for diagnosing a patient with WM require a demonstration of monoclonal IgM in the blood and at least 10 percent of the bone marrow biopsy demonstrating infiltration of small lymphoplasmacytic cells. Many patients are asymptomatic and will receive a diagnosis of WM after receiving lab tests for another reason. Asymptomatic patients can be monitored with regular office visits to assess complete blood counts and monoclonal IgM levels. Symptomatic WM treatment is with a regimen that includes rituximab. As noted, plasmapheresis is necessary if symptoms of hyperviscosity are present, followed by chemotherapy to slow the growth of the malignant clone. A mutation in the gene encoding for MYD88 (MYD88 L265P) is present in over 90% of patients diagnosed with WM, and the identification of this mutation can help distinguish WM from other disorders.[15] Monoclonal gammopathy of undetermined significance (MGUS) is an additional type of monoclonal gammopathy that can result in the overproduction of antibodies, including IgM. MGUS occurs in approximately 1 to 2% of adults, with a higher proportion of cases in men, and the incidence gradually increases with age.[16] MGUS is a clinically asymptomatic premalignant clonal plasma cell that is diagnosable by demonstrating a concentration of monoclonal immunological protein (M protein) of less than 3 grams/dL and fewer than 10 percent of biopsied bone marrow containing infiltrating monoclonal plasma cells. Higher values of M protein or bone marrow infiltration are indicative of multiple myeloma. Additionally, the absence of organ damage caused by the proliferating plasma cells helps further distinguish MGUS from multiple myeloma. Non-IgM MGUS is the most common type of MGUS and is associated with elevated levels of monoclonal IgG, IgA, or IgD. Non-IgM MGUS requires monitoring as the disease has the capability of progressing to multiple myeloma. IgM MGUS accounts for approximately 15% of MGUS cases and is more likely to progress to WM than multiple myeloma. Finally, light chain MGUS represents an additional class of MGUS that is associated with elevated serum M protein that lacks the heavy chain and therefore is only composed of light chains of an immunoglobulin. The depositing of excess monoclonal light chains throughout the body can result in light-chain amyloidosis. Although asymptomatic, all types of MGUS require close monitoring as they each possess a risk for developing into a more advanced lymphoproliferative disorder or malignancy.