A peptide extension dictates IgM assembly

Pasalic, Dzana; Weber, Benedikt; Giannone, Chiara; Anelli, Tiziana; Müller, Roger; Fagioli, Claudio; Felkl, Manuel; John, Christine; Mossuto, Maria F.; Becker, Christian F. W.; Sitia, Roberto; Büchner, Johannes

doi:10.1073/pnas.1701797114

Cited by 21 publications

(27 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The comparable concentrations of IgM and IgG, instead of the higher IgG concentration than IgM, could be due to the presence of different forms of polymerization of IgM molecules (from monomers to pentamers). This is linked to modifications in Ig glycosylation and amino acid composition (25,26). These modifications are frequently described in the case of cryoprecipitating IgM (27).…”

Section: Discussionmentioning

confidence: 99%

Contribution of Hepatitis C Infection to a Large Cohort of Cryoglobulin-Positive Patients: Detection and Characteristics

Kolopp‐Sarda

Miossec

2020

Front. Immunol.

View full text Add to dashboard Cite

Cryoglobulins (CGs) are cold precipitating immunoglobulins, and hepatitis C virus (HCV) infection is its most common cause. The purpose of the study was to determine the contribution of HCV in a large cohort of CG. Biological characteristics and specificity of CGs in HCV patients were compared to non-HCV subjects. Cryoglobulin analysis included isotype, clonality, concentration, and rheumatoid factor (RF) in cryoprecipitate and serum complement and RF. This study is an extension of the study carried out on a cohort of 13,439 patients tested for CGs from all medical units, in which 1,675/13,439 (12.5%) patients had a CG, and 680/1,675 (40.6%) had HCV serology or viral load determination (HCV RNA). Among these 680 CG patients tested for HCV, 325 of 680 (47.8%) HCV patients (272 HCV RNA + and 45 HCV RNA − patients) were compared to 355/680 (52.2%) non-HCV subjects. After a positive detection of CG, HCV status was determined only for 37.7% (256/680) of patients, allowing the diagnosis of a previously unknown HCV infection for 39.8% (102/256). Concentration of HCV RNA + CGs (median = 80.5 mg/L) was significantly higher than that of HCV RNA − CG (median = 50.5 mg/L, p = 0.001) and HCV − CG (median = 32 mg/L, p < 0.0001). There was no difference of median CG concentration between HCV RNA − patients and non-HCV subjects. Rheumatoid factor titer was significantly higher in type II CG compared to type III CG in HCV RNA + patients (254 ± 720 vs. 15 ± 21 IU/mL, p < 0.0001) and non-HCV subjects (333 ± 968 vs. 16.8 ± 26 IU/mL, p = 0.0004). Complement functional activity CH50 was lower in HCV RNA + patients (36 ± 24 U/mL) and in HCV RNA − patients (32 ± 21 U/mL) than in non-HCV subjects (50 ± 25 U/mL, p = 0.001 and p = 0.004). In conclusion, HCV infection and treatment influence CG characteristics. It is essential, and far from always tested, to determine the HCV status of patients with mixed CG, and conversely to search for CG in patients with HCV infection.

show abstract

Section: Discussionmentioning

confidence: 99%

Contribution of Hepatitis C Infection to a Large Cohort of Cryoglobulin-Positive Patients: Detection and Characteristics

Kolopp‐Sarda

Miossec

2020

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…IgM monomers are covalently linked by disulfide bonds between the penultimate cysteine of these tailpiece peptides. The tailpiece peptide is critical for IgM polymerization [ 76 ]. Indeed, the tailpiece can induce the polymerization when fused at the C-terminus of other antibody isotypes such as IgG [ 77 ].…”

Section: Igm Antibody Structurementioning

confidence: 99%

Structure, Function, and Therapeutic Use of IgM Antibodies

et al. 2020

View full text Add to dashboard Cite

Natural immunoglobulin M (IgM) antibodies are pentameric or hexameric macro-immunoglobulins and have been highly conserved during evolution. IgMs are initially expressed during B cell ontogeny and are the first antibodies secreted following exposure to foreign antigens. The IgM multimer has either 10 (pentamer) or 12 (hexamer) antigen binding domains consisting of paired µ heavy chains with four constant domains, each with a single variable domain, paired with a corresponding light chain. Although the antigen binding affinities of natural IgM antibodies are typically lower than IgG, their polyvalency allows for high avidity binding and efficient engagement of complement to induce complement-dependent cell lysis. The high avidity of IgM antibodies renders them particularly efficient at binding antigens present at low levels, and non-protein antigens, for example, carbohydrates or lipids present on microbial surfaces. Pentameric IgM antibodies also contain a joining (J) chain that stabilizes the pentameric structure and enables binding to several receptors. One such receptor, the polymeric immunoglobulin receptor (pIgR), is responsible for transcytosis from the vasculature to the mucosal surfaces of the lung and gastrointestinal tract. Several naturally occurring IgM antibodies have been explored as therapeutics in clinical trials, and a new class of molecules, engineered IgM antibodies with enhanced binding and/or additional functional properties are being evaluated in humans. Here, we review the considerable progress that has been made regarding the understanding of biology, structure, function, manufacturing, and therapeutic potential of IgM antibodies since their discovery more than 80 years ago.

show abstract

“…The secretory forms of both αand μ-HC possess an 18amino-acid-long extension to the C-terminal constant domain, termed the secretory tailpiece (22,23). The tailpiece contains a preterminal cysteine residue, which is the site for the covalent attachment of the J chain to IgA and IgM polymers (24,25) and is necessary for the assembly of dimeric IgA and polymeric IgM (26). Quality control of sIgA and IgM assembly in the endoplasmic reticulum (ER) requires the tailpiece (27).…”

mentioning

confidence: 99%

MZB1 promotes the secretion of J-chain–containing dimeric IgA and is critical for the suppression of gut inflammation

Xiong

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

IgA is the most abundantly produced antibody in the body and plays a crucial role in gut homeostasis and mucosal immunity. IgA forms a dimer that covalently associates with the joining (J) chain, which is essential for IgA transport into the mucosa. Here, we demonstrate that the marginal zone B and B-1 cell-specific protein (MZB1) interacts with IgA through the α-heavy-chain tailpiece dependent on the penultimate cysteine residue and prevents the intracellular degradation of α-light-chain complexes. Moreover, MZB1 promotes J-chain binding to IgA and the secretion of dimeric IgA. MZB1-deficient mice are impaired in secreting large amounts of IgA into the gut in response to acute inflammation and develop severe colitis. Oral administration of a monoclonal IgA significantly ameliorated the colitis, accompanied by normalization of the gut microbiota composition. The present study identifies a molecular chaperone that promotes J-chain binding to IgA and reveals an important mechanism that controls the quantity, quality, and function of IgA.

show abstract

A peptide extension dictates IgM assembly

Cited by 21 publications

References 43 publications

Contribution of Hepatitis C Infection to a Large Cohort of Cryoglobulin-Positive Patients: Detection and Characteristics

Contribution of Hepatitis C Infection to a Large Cohort of Cryoglobulin-Positive Patients: Detection and Characteristics

Structure, Function, and Therapeutic Use of IgM Antibodies

MZB1 promotes the secretion of J-chain–containing dimeric IgA and is critical for the suppression of gut inflammation

Contact Info

Product

Resources

About