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Nature Structural & Molecular Biology Jul 2023Immunoglobulin Fc receptors are cell surface transmembrane proteins that bind to the Fc constant region of antibodies and play critical roles in regulating immune...
Immunoglobulin Fc receptors are cell surface transmembrane proteins that bind to the Fc constant region of antibodies and play critical roles in regulating immune responses by activation of immune cells, clearance of immune complexes and regulation of antibody production. FcμR is the immunoglobulin M (IgM) antibody isotype-specific Fc receptor involved in the survival and activation of B cells. Here we reveal eight binding sites for the human FcμR immunoglobulin domain on the IgM pentamer by cryogenic electron microscopy. One of the sites overlaps with the binding site for the polymeric immunoglobulin receptor (pIgR), but a different mode of FcμR binding explains its antibody isotype specificity. Variation in FcμR binding sites and their occupancy reflects the asymmetry of the IgM pentameric core and the versatility of FcμR binding. The complex explains engagement with polymeric serum IgM and the monomeric IgM B-cell receptor (BCR).
Topics: Humans; Receptors, Fc; B-Lymphocytes; Immunoglobulin Fc Fragments; Immunoglobulin M; Binding Sites
PubMed: 37095205
DOI: 10.1038/s41594-023-00985-x -
Biological & Pharmaceutical Bulletin 2013In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit... (Review)
Review
In contrast to the general assumption that polyethyleneglycol (PEG)-conjugated substances lack immunogenicity and antigenic, it has been reported that they can elicit antibodies against PEG (mainly anti-PEG immunoglobulin M (IgM)). In patients, the presence of anti-PEG antibodies may limit therapeutic efficacy of PEGylated substances as a consequence of inducing rapid clearance of and neutralizing biological activity of the substances. Here, we introduce specific examples of PEGylated substances including several PEGylated proteins and PEGylated particles (PEGylated nanocarriers) which induce anti-PEG antibody responses. Finally, we emphasize that the immunogenicity of PEGylated substances should be tested in the development stage and that the titer of anti-PEG antibodies in patients should be pre-screened and monitored prior to and throughout a course of treatment with a PEGylated substance.
Topics: Animals; Drug Carriers; Humans; Immunoglobulin M; Nanoparticles; Pharmaceutical Preparations; Polyethylene Glycols; Proteins
PubMed: 23727911
DOI: 10.1248/bpb.b13-00107 -
Clinical Microbiology Reviews Jul 1990Serologic tests have assisted in the diagnosis and prognosis of coccidioidomycosis for a half-century. The causative agent, Coccidioides immitis, is a dimorphic fungus... (Review)
Review
Serologic tests have assisted in the diagnosis and prognosis of coccidioidomycosis for a half-century. The causative agent, Coccidioides immitis, is a dimorphic fungus existing in a hyphal form with arthroconidia in nature and in the usual culture. The arthroconidia represent the inhaled infective forms which in vivo and under special laboratory conditions form spherules which endosporulate. The culture filtrate/autolysate (coccidioidin) from the hyphal phase has provided antigens of suitable reliability for currently used serologic tests. These tests are primarily to determine the two major antibody responses: the early immunoglobulin M (IgM) response is useful in the diagnosis of acute primary coccidioidomycosis. Later, IgG is produced and usually outlasts the IgM, persisting in chronic coccidioidomycosis. The IgM is detectable by tube precipitin, a corresponding immunodiffusion, or latex particle agglutination tests. The pertinent antigen(s) is heat stable and pronase resistant and appears to be largely carbohydrate, mainly mannose with some 3-O-methyl mannose. The IgG detectable in the serum and other body fluids by complement fixation and a corresponding immuno-diffusion is useful in diagnosis, and its quantitation provides an indicator of progression of disease (increasing titer) or regression (decreasing titer). The pertinent antigen appears to be a heat-labile, pronase-sensitive protein which in an unreduced form has a molecular weight of 110,000. A third very useful serologic procedure is the exoantigen test for identification of putative cultures of C. immitis.
Topics: Animals; Antibodies, Fungal; Antigens, Fungal; Coccidioides; Coccidioidomycosis; Cross Reactions; Humans; Immunoglobulin G; Immunoglobulin M; Prognosis
PubMed: 2200605
DOI: 10.1128/CMR.3.3.247 -
Clinical and Vaccine Immunology : CVI Jul 2016Immunoglobulin M (IgM) tests have clear clinical utility but also suffer disproportionately from false-positive results, which in turn can lead to misdiagnoses,... (Review)
Review
Immunoglobulin M (IgM) tests have clear clinical utility but also suffer disproportionately from false-positive results, which in turn can lead to misdiagnoses, inappropriate therapy, and premature closure of a diagnostic workup. Despite numerous reports in the literature, many clinicians and laboratorians remain unaware of this issue. In this brief review, a series of virology case examples is presented. However, a false-positive IgM can occur with any pathogen. Thus, when an accurate diagnosis is essential for therapy, prognosis, infection control, or public health, when the patient is sick enough to be hospitalized, or when the clinical or epidemiologic findings do not fit, IgM detection should not be accepted as a stand-alone test. Rather, whenever possible, the diagnosis should be confirmed by other means, including testing of serial samples and the application of additional test methods.
Topics: Communicable Diseases; False Positive Reactions; Humans; Immunoglobulin M; Sensitivity and Specificity; Serologic Tests
PubMed: 27193039
DOI: 10.1128/CVI.00211-16 -
Arthritis Research & Therapy Jul 2012Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE)... (Review)
Review
Immunoglobulin class-switch recombination deficiencies (Ig-CSR-Ds) are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect in question, the Ig-CSR-D may be combined with an impairment in somatic hypermutation (SHM). Some of the mechanisms underlying Ig-CSR and SHM have been described by studying natural mutants in humans. This approach has revealed that T cell-B cell interaction (resulting in CD40-mediated signaling), intrinsic B-cell mechanisms (activation-induced cytidine deaminase-induced DNA damage), and complex DNA repair machineries (including uracil-N-glycosylase and mismatch repair pathways) are all involved in class-switch recombination and SHM. However, several of the mechanisms required for full antibody maturation have yet to be defined. Elucidation of the molecular defects underlying the diverse set of Ig-CSR-Ds is essential for understanding Ig diversification and has prompted better definition of the clinical spectrum of diseases and the development of increasingly accurate diagnostic and therapeutic approaches.
Topics: Animals; Humans; Immunoglobulin Class Switching; Immunoglobulin M; Immunologic Deficiency Syndromes; Recombination, Genetic
PubMed: 22894609
DOI: 10.1186/ar3904 -
Structure (London, England : 1993) Jun 2021Immunoglobulins (Ig) A and M are the only human antibodies that form oligomers and undergo transcytosis to mucosal secretions via the polymeric Ig receptor (pIgR). When...
Immunoglobulins (Ig) A and M are the only human antibodies that form oligomers and undergo transcytosis to mucosal secretions via the polymeric Ig receptor (pIgR). When complexed with the J-chain (JC) and the secretory component (SC) of pIgR, secretory IgA and IgM (sIgA and sIgM) play critical roles in host-pathogen defense. Recently, we determined the structure of sIgA-Fc which elucidated the mechanism of polymeric IgA assembly and revealed an extensive binding interface between IgA-Fc, JC, and SC. Despite low sequence identity shared with IgA-Fc, IgM-Fc also undergoes JC-mediated assembly and binds pIgR. Here, we report the structure of sIgM-Fc and carryout a systematic comparison to sIgA-Fc. Our structural analysis reveals a remarkably conserved mechanism of JC-templated oligomerization and SC recognition of both IgM and IgA through a highly conserved network of interactions. These studies reveal the structurally conserved features of sIgM and sIgA required for function in mucosal immunity.
Topics: Cell Line; Humans; Immunoglobulin A, Secretory; Immunoglobulin J-Chains; Immunoglobulin M; Models, Molecular; Protein Conformation; Secretory Component; Structural Homology, Protein; Transcytosis
PubMed: 33513362
DOI: 10.1016/j.str.2021.01.002 -
The Journal of Experimental Medicine Dec 2018In this issue of , Thierry et al. (https://doi.org/10.1084/jem.20180344) demonstrate that, once secreted by freshly activated plasmablasts, IgM leaves the lymph node via...
In this issue of , Thierry et al. (https://doi.org/10.1084/jem.20180344) demonstrate that, once secreted by freshly activated plasmablasts, IgM leaves the lymph node via the microarchitecture of the fibroblastic reticular cell conduit. This work demonstrates how the very peculiar stromal compartment of lymphatic organs optimizes the systemic distribution of immune effectors.
Topics: Fibroblasts; Immunoglobulin M; Lymph Nodes
PubMed: 30459158
DOI: 10.1084/jem.20181934 -
Critical Reviews in Immunology 2016Most serum immunoglobulin M (IgM) is "natural IgM", which is produced apparently spontaneously by a distinct subset of B cells requiring no exogenous antigenic or... (Review)
Review
Most serum immunoglobulin M (IgM) is "natural IgM", which is produced apparently spontaneously by a distinct subset of B cells requiring no exogenous antigenic or microbial stimuli. Natural IgM is an evolutionarily conserved molecule and reacts with a variety of epitopes expressed on both self- and non-self antigens. It has long been understood that secreted (s) IgM contributes to the removal of altered self-antigens, such as apoptotic and dying cells. As we outline in this review, it is thought that this sIgM housekeeping function removes potential triggers of autoresponse induction. However, we recently demonstrated an unexpected and distinct role for sIgM in the control of autoreactive B cells: the regulation of bone marrow B cell development. The absence of sIgM blocked pro- to pre- B-cell transition and greatly altered the BCR repertoire of the developing B cells and the peripheral B-cell pools in genetically engineered mice. This finding strongly suggests that IgM is critical for B-cell central tolerance induction. Given that treatment of sIgM-deficient mice with polyclonal IgM corrected these developmental defects, therapeutic application of IgM could be of clinical relevance in the treatment of some B-cell-mediated autoimmune diseases.
Topics: Animals; Autoimmune Diseases; B-Lymphocytes; Humans; Immunoglobulin M
PubMed: 27910766
DOI: 10.1615/CritRevImmunol.2016018175 -
CEN Case Reports Aug 2021Selective immunoglobulin M deficiency (SIgMD) is the isolated absence of serum immunoglobulin M (IgM) with normal levels of other serum immunoglobulins. SIgMD is... (Review)
Review
Selective immunoglobulin M deficiency (SIgMD) is the isolated absence of serum immunoglobulin M (IgM) with normal levels of other serum immunoglobulins. SIgMD is associated with infections and autoimmune diseases. While there are few reports on SIgMD complicated by systemic lupus erythematosus (SLE), there are no reports on SIgMD complicated by SLE and antiphospholipid syndrome (APS); we present the first report of this kind. A 61-year-old Japanese woman presented with microscopic hematuria and proteinuria. Clinical investigations revealed an elevated serum creatinine level, an undetectable serum IgM level, and seropositivity of antinuclear antibody, anti-Smith antibody, and double-stranded DNA antibody. Radiological investigations were unremarkable. Renal biopsy revealed focal and segmental mesangial cell proliferation; thickened glomerular capillary walls; and IgG, IgA, C3, and C1q deposition, which indicated class III (A/C) lupus nephritis (Renal Pathology Society/International Society of Nephrology classification). Furthermore, anti-CLβ2GP1 antibody positivity and deep vein thrombosis were noted, which fulfilled the revised Sapporo classification criteria for the diagnosis of APS. Thus, she was diagnosed with SIgMD complicated by SLE and APS. The patient was treated with prednisolone, mycophenolate mofetil, and warfarin. After a 1-year follow-up, she achieved clinical remission of SLE and APS without infectious complications; however, the serum IgM level remained undetectable. In conclusion, SIgMD can be complicated by autoimmune disorders. Although rare, we recommend that SLE and APS be considered in patients with SIgMD who present with hematuria, proteinuria, and deep vein thrombosis. We also recommend measuring the titers of antinuclear antibodies, double-stranded DNA antibodies, and anti-CLβ2GP1 antibodies.
Topics: Antiphospholipid Syndrome; Female; Humans; Immunoglobulin M; Lupus Erythematosus, Systemic; Middle Aged
PubMed: 33616883
DOI: 10.1007/s13730-021-00583-0 -
Oral Diseases Nov 2022To assess the accuracy of three immunochromatographic rapid tests for salivary detection of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against severe...
OBJECTIVES
To assess the accuracy of three immunochromatographic rapid tests for salivary detection of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens and the reliability of these tests comparing saliva with plasma samples.
MATERIALS AND METHODS
Plasma and saliva samples from 62 patients diagnosed with coronavirus disease 2019 (COVID-19) and 20 healthy volunteers were assayed. IgM/IgG antibody against SARS-COV-2 was detected using three immunochromatographic rapid tests and compared with real-time reverse transcription-polymerase chain reaction (qRT-PCR).
RESULTS
The tests' overall accuracy for detecting anti-SARS-CoV-2 antibodies ranged from 75.6 to 79.3 for saliva and 86.6-87.8 for plasma tests. The sensitivity of saliva and plasma tests increased with the severity of COVID-19 signs and symptoms. The chance of a positive plasma test in participants with a positive qRT-PCR test was 2.27 greater than a positive saliva test.
CONCLUSIONS
Although rapid immunochromatographic tests are more accurate using plasma than saliva, which was expected considering its original use, our findings support the use of saliva as a straightforward supplementary method to assess seroconversion in patients with COVID-19, with important sensitivity and sensibility, especially in severe and critical cases.
Topics: Humans; COVID-19; Immunoglobulin G; SARS-CoV-2; Reproducibility of Results; Immunoglobulin M; Sensitivity and Specificity
PubMed: 34695290
DOI: 10.1111/odi.14059