The presence of immunoglobulin A (IgA) autoantibodies has been described in many autoimmune diseases, and some of its characteristics, such as IgA dimerization, are considered a sign of a mucosal origin. However, limited information is available about the (patho)physiological conditions leading to the development of monomeric vs dimeric (autoreactive) IgA in humans. Therefore, we investigated IgA dimerization in rheumatic autoimmune diseases with a possible mucosal origin, as well as after vaccination.
Plasma of patients with rheumatic disease (rheumatoid arthritis [RA], systemic sclerosis [SSc], anti-neutrophil cytoplasmic antibody associated vasculitis [AAV], systemic lupus erythematosus [SLE]), SARS-CoV-2 vaccinated healthy individuals, and healthy controls was used for size exclusion chromatography (SEC). Enzyme-linked immunosorbent assays were performed on SEC fractions to determine the size of IgA. Results were confirmed using western blot and tandem mass spectrometry.
The proportion of dimeric IgA was increased for autoantibodies compared to total IgA. This was most evident in RA, AAV, and SLE (dimeric autoreactive IgA ≈ 60%-80% vs total IgA ≈ 20%, SLE ≈ 60% total IgA), but not in SSc. Intramuscular vaccination against SARS-CoV-2 also led to an increased proportion of dimeric anti-spike IgA shortly after vaccination, irrespective of previous mucosal exposure.
These findings indicate that dimeric (autoreactive) IgA responses are associated with newly emerging antigen-specific immune activation, where production temporarily shifts to dimeric IgA. Mucosal triggering is not necessarily always involved in these IgA immune responses. These findings provide key insights into the circumstances for IgA dimerization and suggest that dimeric IgA could serve as a marker for immunological disease activity in autoimmunity.
Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.

Tuberculosis (TB) remains a major cause of global mortality. Understanding the underlying immune response to the pathogen, Mycobacterium tuberculosis (Mtb), is essential for the development of vaccines. Evidence is accumulating supporting a contribution of innate immune cells and antibodies in Mtb control. Here, we focus on the functional capacity of antibodies from individuals with TB disease, both before and after TB treatment, individuals with TB infection, and healthy uninfected individuals, using an adapted in vitro mycobacterial growth inhibition assay, measuring Bacillus Calmette-Guérin (BCG) growth inhibition. Sera displayed heterogeneous impact on mycobacterial growth control. This was correlated with enhanced phagocytic capacity, which was abrogated by blocking Fc receptors (FcR) and depletion of antibodies. This phenotype negatively associated with mono- and digalactosylated Fc-glycans of IgG. Together, we demonstrate disease state independent direct effects of sera to mycobacterial growth control and antibody-FcR interactions modulating phagocytic capacity.
© 2025 The Author(s).

The development of antibody drugs through animal immunization typically requires the humanization of host antibodies to address concerns about immunogenicity in humans. However, employing an animal model capable of producing human antibodies presents the opportunity to develop antibody drugs without the need for humanization. Despite the ratio of human immunoglobulin (Ig) κ to Igλ usage being approximately 60%:40%, the majority of approved antibody therapeutics are kappa antibodies, and the development of lambda antibodies as therapeutic agents has lagged behind. Therefore, in this study, we developed mice carrying the IGH and IGL loci (IGHL), which can produce human lambda antibodies, using mouse artificial chromosome (MAC) vectors. We demonstrated that IGHL mice consistently retain the human lambda antibody locus integrated on the MAC across generations and can be induced to produce specific antibodies upon antigen stimulation. These findings provide a promising platform for advancing lambda antibody drugs, which have historically been neglected.
© 2024 The Author(s).

The COVID-19 pandemic has had a major impact on global health and economy, which was significantly mitigated by the availability of COVID-19 vaccines. The levels of systemic and mucosal antibodies against SARS-CoV-2 correlated with protection. However, there is limited data on how vaccine type and booster doses affect mucosal antibody response, and how the breadth of mucosal and systemic antibodies compares. In this cross-sectional study, we compared the magnitude and breadth of mucosal and systemic antibodies in 108 individuals who received either the BNT162b2 (Pfizer) or CoronaVac (SinoVac) vaccine. We found that BNT162b2 (vs CoronaVac) or booster doses (vs two doses) were significantly associated with higher serum IgG levels, but were not significantly associated with salivary IgA levels, regardless of prior infection status. Among non-infected individuals, serum IgG, serum IgA and salivary IgG levels were significantly higher against the ancestral strain than the Omicron BA.2 sublineage, but salivary IgA levels did not differ between the strains. Salivary IgA had the weakest correlation with serum IgG (r = 0.34) compared with salivary IgG (r = 0.63) and serum IgA (r = 0.60). Our findings suggest that intramuscular COVID-19 vaccines elicit a distinct mucosal IgA response that differs from the systemic IgG response. As mucosal IgA independently correlates with protection, vaccine trials should include mucosal IgA as an outcome measure.
© 2024 The Authors. Published by Elsevier Ltd.

Mucosal immunity may contribute to clearing SARS-CoV-2 infection prior to systemic infection, thereby allowing hosts to remain seronegative. We describe the meaningful detection of SARS-CoV-2-specific nasal mucosal antibodies in a group of exposed-household individuals that evaded systemic infection. Between June 2020 and February 2023, nasopharyngeal swab (NPS) and acute and convalescent blood were collected from individuals exposed to a SARS-CoV-2-confirmed household member. Nasal secretory IgA (SIgA) antibodies targeting the SARS-CoV-2 spike protein were measured using a modified ELISA. Of the 36 exposed individuals without SARS-CoV-2 detected by the RT-PCR of NPS specimens and seronegative for SARS-CoV-2-specific IgG at enrollment and convalescence, 13 (36.1%) had positive SARS-CoV-2-specific SIgA levels detected in the nasal mucosa at enrollment. These individuals had significantly higher nasal SIgA (median 0.52 AU/mL) compared with never-exposed, never-infected controls (0.001 AU/mL) and infected-family participants (0.0002 AU/mL) during the acute visit, respectively (both p < 0.001). The nasal SARS-CoV-2-specific SIgA decreased rapidly over two weeks in the exposed seronegative individuals compared to a rise in SIgA in infected-family members. The nasal SARS-CoV-2-specific SIgA may have a protective role in preventing systemic infection.