IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4⁺ and CD8⁺ T cells with a T_h1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate.

The coronavirus disease 2019 (COVID-19) pandemic has illustrated the critical need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive approach for preventing COVID-19 as the nasal mucosa is the site of initial SARS-CoV-2 entry and viral replication prior to aspiration into the lungs. We previously demonstrated that a single intranasal administration of a candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain of the SARS-CoV-2 spike protein (AdCOVID) induced robust immunity in both the airway mucosa and periphery, and completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge. Here we show that a single intranasal administration of AdCOVID limits viral replication in the nasal cavity of K18-hACE2 mice. AdCOVID also induces sterilizing immunity in the lungs of mice as reflected by the absence of infectious virus. Finally, AdCOVID prevents SARS-CoV-2 induced pathological damage in the lungs of mice. These data show that AdCOVID not only limits viral replication in the respiratory tract, but it also prevents virus-induced inflammation and immunopathology following SARS-CoV-2 infection.

The triggering receptor expressed on myeloid cell locus encodes a family of receptors that is emerging as an important class of molecules involved in modulating the innate immune response and inflammation. Of the 4 conserved members, including triggering receptor expressed on myeloid cells 1 and 2 and triggering receptor expressed on myeloid cell-like transcripts 1 and 2, relatively little is known about triggering receptor expressed on myeloid cell-like transcript 2 expression and function, particularly in humans. In this study, experiments were performed to determine if triggering receptor expressed on myeloid cell-like transcript 2 expression is conserved between mouse and human, demonstrating that human triggering receptor expressed on myeloid cell-like transcript 2 is expressed on cells of the lymphoid, as well as myeloid/granuloid lineages, similar to murine triggering receptor expressed on myeloid cell-like transcript 2. Consistent with studies in the mouse, triggering receptor expressed on myeloid cell-like transcript 2 expression is up-regulated in response to inflammatory mediators on human neutrophils. Importantly, it was shown that triggering receptor expressed on myeloid cell-like transcript 2, in resting human neutrophils, is predominantly localized to intracellular vesicles, including secretory vesicles and primary granules; with the majority of triggering receptor expressed on myeloid cell-like transcript 2 stored in primary granules. In contrast to other primary granule proteins, triggering receptor expressed on myeloid cell-like transcript 2 is not expelled on neutrophil extracellular traps but is retained in the plasma membrane following primary granule exocytosis. In summary, these findings establish that triggering receptor expressed on myeloid cell-like transcript 2 expression is conserved between species and is likely to be important in regulating neutrophil antimicrobial function following primary granule exocytosis.

IgA nephropathy is a kidney disease characterized by deposition of immune complexes containing abnormally O-glycosylated IgA1 in the glomeruli. Specifically, some O-glycans are missing galactose that is normally β1,3-linked to N-acetylgalactosamine of the core 1 glycans. These galactose-deficient IgA1 glycoforms are produced by IgA1-secreting cells due to a dysregulated expression and activity of several glycosyltransferases. Galactose-deficient IgA1 in the circulation of patients with IgA nephropathy is bound by IgG autoantibodies and the resultant immune complexes can contain additional proteins, such as complement C3. These complexes, if not removed from the circulation, can enter the glomerular mesangium, activate the resident mesangial cells, and induce glomerular injury. In this review, we briefly summarize clinical and pathological features of IgA nephropathy, review normal and aberrant IgA1 O-glycosylation pathways, and discuss the origins and potential significance of natural anti-glycan antibodies, namely those recognizing N-acetylgalactosamine. We also discuss the features of autoantibodies specific for galactose-deficient IgA1 and the characteristics of pathogenic immune complexes containing IgA1 and IgG. In IgA nephropathy, kidneys are injured by IgA1-containing immune complexes as innocent bystanders. Most patients with IgA nephropathy progress to kidney failure and require dialysis or transplantation. Moreover, most patients after transplantation experience a recurrent disease. Thus, a better understanding of the pathogenetic mechanisms is needed to develop new disease-specific treatments.