Immunoglobulin A nephropathy is characterized by anticommensal humoral immune responses.

IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production are not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries with high disease prevalence, tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses, we characterized the tonsil microbiota in patients with IgAN versus nonrelated household-matched control group participants and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN patients. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B × hC-Tg). Colonization of B × hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria-specific IgA-secreting cells within the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts, such as Neisseria, in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.

Exploring the Ability of Meningococcal Vaccines to Elicit Mucosal Immunity: Insights from Humans and Mice.

Neisseria meningitidis causes a devastating invasive disease but is also a normal colonizer of the human nasopharynx. Due to the rapid progression of disease, the best tool to protect individuals against meningococcal infections is immunization. Clinical experience with polysaccharide conjugate vaccines has revealed that an ideal meningococcal vaccine must prevent both invasive disease and nasal colonization, which confers herd immunity. However, not all meningococcal vaccines are equal in their ability to prevent nasal colonization, for unknown reasons. Herein, we describe recent efforts to utilize humanized mouse models to understand the impact of different meningococcal vaccines on nasal colonization. These mice are susceptible to nasal colonization, and they become immune following live nasal infection or immunization with matched capsule-conjugate or protein-based vaccines, replicating findings from human work. We bring together insights regarding meningococcal colonization and immunity from clinical work with findings using humanized mouse models, providing new perspective into the different determinants of mucosal versus systemic immunity. Then, we use this as a framework to help focus future studies toward understanding key mechanistic aspects left unresolved, including the bacterial factors required for colonization and immune evasion, determinants of nasal mucosal protection, and characteristics of an ideal meningococcal vaccine.

Discordant Effects of Licensed Meningococcal Serogroup B Vaccination on Invasive Disease and Nasal Colonization in a Humanized Mouse Model.

Background: The multicomponent meningococcal serogroup B vaccine (4CMenB) is an outer membrane vesicle and recombinant protein-based vaccine licensed to protect against serogroup B meningococcal disease. It remains unknown whether this vaccine will prevent carriage or transmission, key aspects in long-term vaccine success and disease eradication. Methods: Using a "humanized" transgenic mouse model of nasal colonization, we took a systematic approach to estimate the potential for carriage prevention against antigenically diverse Neisseria meningitidis strains and to compare this protection to an invasive meningococcal disease challenge model. Results: The 4CMenB vaccine prevented morbidity and mortality after lethal invasive doses of all meningococcal strains tested. Immunization effectively prevented carriage with only 1 of 4 single antigen-matched strains but reduced or prevented nasal colonization by all 4 isolates with multiple cross-reacting antigens. Each immunized mouse had substantial immunoglobulin G targeting the challenge strains, indicating that antibody correlates with protection against sepsis but not nasal carriage. Conclusions: Immunization with the 4CMenB vaccine elicits a robust humoral response that correlates with protection against invasive challenge but not with prevention of asymptomatic colonization. This suggests that widespread use of this vaccine will reduce morbidity and mortality rates in immunized individuals, with the potential to contribute to herd protection against a subset of strains.