IgA subclasses have different effector functions associated with distinct glycosylation profiles

Steffen, Ulrike; Koeleman, Carolien A. M.; Sokolova, Maria; Bang, Holger; Kleyer, Arnd; Rech, Jürgen; Unterweger, Harald; Schicht, Martin; Garreis, Fabian; Hahn, Jonas; Andes, Fabian T.; Hartmann, F; Hahn, Madelaine; Mahajan, Aparna; Paulsen, Friedrich; Hoffmann, Markus; Lochnit, Günter; Muñoz, Luis E.; Wuhrer, Manfred; Falck, David; Herrmann, Martin; Schett, Georg

doi:10.1038/s41467-019-13992-8

Cited by 182 publications

(196 citation statements)

References 58 publications

Supporting

Mentioning

179

Contrasting

Unclassified

Order By: Relevance

“…Speculatively, our results may suggest that mucosal immunization to citrullinated proteins are particularly relevant in compartments with pronounced IgA2 dominance, such as the lower gastrointestinal tract [ 12 , 28 ]. Although total IgA2 in serum has recently been found to be more pro-inflammatory than IgA1 in vitro [ 29 ], we could not see any difference between serum IgA1 ACPA and IgA2 ACPA regarding their association to disease activity. In the saliva, the reverse was noticed with higher disease activity among IgA1 ACPA-positive patients.…”

Section: Discussioncontrasting

confidence: 87%

Presence of salivary IgA anti-citrullinated protein antibodies associate with higher disease activity in patients with rheumatoid arthritis

et al. 2020

View full text Add to dashboard Cite

Background Circulating IgA anti-citrullinated protein antibodies (ACPA) associate with more active disease, but a previous study implied that salivary IgA ACPA is related to a less severe disease. Therefore, we aimed to characterize the IgA ACPA response in the saliva and serum in relation to clinical picture and risk factors among patients with rheumatoid arthritis (RA). Methods RA patients (n = 196) and healthy blood donors (n = 101), included in the cross-sectional study “Secretory ACPA in Rheumatoid Arthritis” (SARA), were analyzed for ACPA of IgA isotype, and for subclasses IgA1 and IgA2 ACPA in paired saliva and serum samples using modified enzyme-linked immunosorbent assays (ELISA) targeting reactivity to a cyclic citrullinated peptide (anti-CCP). Cutoff levels for positive tests were set at the 99th percentile for blood donors. Antibody levels were related to clinical characteristics, radiographic damage, smoking habits, and carriage of HLA-DRB1/shared epitope (SE). Results IgA ACPA in the saliva was found in 12% of RA patients, IgA1 occurred in 10%, and IgA2 in 9%. In serum, IgA ACPA was found in 45% of the patients, IgA1 in 44%, and IgA2 in 39%. Levels of IgA ACPA in the saliva correlated significantly with serum levels of IgA (r = 0.455). The presence of salivary IgA ACPA was associated with a higher erythrocyte sedimentation rate (ESR), 28-joint disease activity score, tender joint count, and patient global assessment at the time of sampling. None of the antibodies was associated with smoking, SE, or radiographic damage. Conclusion Salivary IgA ACPAs were detected in a subset of RA patients in association with higher disease activity. This suggests that mucosal ACPA responses in the oral cavity may contribute to disease-promoting processes in RA.

show abstract

Section: Discussioncontrasting

confidence: 87%

Presence of salivary IgA anti-citrullinated protein antibodies associate with higher disease activity in patients with rheumatoid arthritis

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In this study we examined factors that affect the dimeric IgA formation in N. benthamiana which is currently one of the most widely used plant for recombinant protein expression and glyco-engineering (Bally et al, 2018;Montero-Morales and Steinkellner, 2018). IgAs are heavily glycosylated and distinct glycoforms contribute to the overall thermal stability of IgAs (Göritzer et al, 2017), the in vivo halflife (Rouwendal et al, 2016) and effector functions (Steffen et al, 2020). Moreover, not only is the N-as well as Oglycan composition different between plant-and mammalian cell-derived IgAs, but also the degree of glycosylation in the single tailpiece N-glycosylation site (Göritzer et al, 2017;Castilho et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Efficient N-Glycosylation of the Heavy Chain Tailpiece Promotes the Formation of Plant-Produced Dimeric IgA

et al. 2020

View full text Add to dashboard Cite

Production of monomeric IgA in mammalian cells and plant expression systems such as Nicotiana benthamiana is well-established and can be achieved by co-expression of the corresponding light and heavy chains. In contrast, the assembly of dimeric IgA requires the additional expression of the joining chain and remains challenging especially in plant-based systems. Here, we examined factors affecting the assembly and expression of HER2 binding dimeric IgA1 and IgA2m(2) variants transiently produced in N. benthamiana. While co-expression of the joining chain resulted in efficient formation of dimeric IgAs in HEK293F cells, a mixture of monomeric, dimeric and tetrameric variants was detected in plants. Mass-spectrometric analysis of site-specific glycosylation revealed that the N-glycan profile differed between monomeric and dimeric IgAs in the plant expression system. Co-expression of a single-subunit oligosaccharyltransferase from the protozoan Leishmania major in N. benthamiana increased the N-glycosylation occupancy at the C-terminal heavy chain tailpiece and changed the ratio of monomeric to dimeric IgAs. Our data demonstrate that N-glycosylation engineering is a suitable strategy to promote the formation of dimeric IgA variants in plants.

show abstract

“…Equally, IgA Fc region characteristics may determine IgA passive transfer or effector function in breast milk (Goonatilleke et al, 2019;Langel et al, 2020;Steffen et al, 2020). Of note, the glycosylation pattern of IgA antibodies is more complex, extensive and diverse; IgA2 is found at a higher percentage in mucosal secretions and has a great number of conserved N-glycans compared to IgA1, which dominates in serum (Mattu et al, 1998).…”

Section: Factors Affecting Maternal Antibody Transfer In Breast Milkmentioning

confidence: 99%

Maternal Immunization: Nature Meets Nurture

Saso

Kampmann

2020

Front. Microbiol.

View full text Add to dashboard Cite

Vaccinating women in pregnancy (i.e., maternal immunization) has emerged as a promising tool to tackle infant morbidity and mortality worldwide. This approach nurtures a 'gift of nature,' whereby antibody is transferred from mother to fetus transplacentally during pregnancy, or postnatally in breast milk, thereby providing passive, antigenspecific protection against infections in the first few months of life, a period of increased immune vulnerability for the infant. In this review, we briefly summarize the rationale for maternal immunization programs and the landscape of vaccines currently in use or in the pipeline. We then direct the focus to the underlying biological phenomena, including the main mechanisms by which maternally derived antibody is transferred efficiently to the infant, at the placental interface or in breast milk; important research models and methodological approaches to interrogate these processes, particularly in the context of recent advances in systems vaccinology; the potential biological and clinical impact of high maternal antibody titres on neonatal ontogeny and subsequent infant vaccine responses; and key vaccine-and host-related factors influencing the maternal-infant dyad across different environments. Finally, we outline important gaps in knowledge and suggest future avenues of research on this topic, proposing potential strategies to ensure optimal testing, delivery and implementation of maternal vaccination programs worldwide.

show abstract

IgA subclasses have different effector functions associated with distinct glycosylation profiles

Cited by 182 publications

References 58 publications

Presence of salivary IgA anti-citrullinated protein antibodies associate with higher disease activity in patients with rheumatoid arthritis

Presence of salivary IgA anti-citrullinated protein antibodies associate with higher disease activity in patients with rheumatoid arthritis

Efficient N-Glycosylation of the Heavy Chain Tailpiece Promotes the Formation of Plant-Produced Dimeric IgA

Maternal Immunization: Nature Meets Nurture

Contact Info

Product

Resources

About