Induction of antigen-specific IGA in the GUT

The National Institute of Allergy and Infectious Diseases awarded Northwestern University a $1,279,395 cooperative agreement on August 1, 2026, to investigate fundamental mechanisms governing the induction of antigen-specific IgA in the gastrointestinal tract under the Allergy and Infectious Diseases Research program (CFDA 93.855).

The research project examines two distinct pathways generating affinity-matured gut IgA following oral immunization with protein antigens. The first pathway, operating within the initial weeks of immunization, is T cell dependent but germinal center-independent, generating antigen-specific IgA from IgM precursors. The second pathway, appearing after multiple weeks, is germinal center-dependent and generates IgA from IgG1+ precursor B cells through sequential class switch recombination. Aim 1 determines the requirement for sequential class switching in producing high-affinity IgA in the gut, evaluating impacts on IgA antibody kinetics, quality, and B cell differentiation, with identification of sequential class switch recombination locations within mouse and human Peyer's patches using imaging and spatial transcriptomics. Aim 2 defines the role of germinal center dynamics in supporting protective IgA responses.

Work is performed in Chicago, Illinois. The period of performance extends from August 1, 2026, through June 30, 2031.

Abstract

IGA is the dominant antibody isotype protecting mucosal surfaces, such as the respiratory and gastrointestinal tracts. However, fundamental mechanisms governing the induction of antigen-specific IGA remain poorly understood. As a result, our ability to harness IGA for clinical benefit is limited: (1) most vaccines fail to elicit IGA; (2) although immunotherapy for food allergy increases IGA levels, the protective function of this IGA remains uncertain; and (3) dysregulated GUT IGG has been implicated in inflammatory bowel disease, but its relationship to concurrent IGA responses is unknown we discovered two distinct pathways generating affinity-matured GUT IGA following oral immunization with protein antigens in mice. Over the first few weeks of immunization, a t cell dependent, but t follicular helper (TFH)- and germinal center-independent pathway generates antigen- specific IGA from IGM precursors, providing a first wave of mucosal IGA. After multiple weeks, a second wave of IGA+ plasma cells and memory b cells appear that are germinal center-dependent. Surprisingly, this second wave of IGA is generated from IGG1+ precursor b cells, thus requiring sequential class switch recombination (CSR). We hypothesize sequential CSR through a TFH driven, germinal center-dependent, IGG1+ b cell stage is required to support maximally protective, high affinity IGA+ plasma cell and memory responses; importantly, this second phase links mucosal IGA and circulating IGG specificity to GUT-derived antigens. In aim 1 we will determine the requirement for sequential class switching in producing high-affinity IGA in the GUT. We will evaluate the impact of impaired sequential CSR on IGA antibody kinetics, quality, and b cell differentiation. In addition, using imaging and spatial transcriptomics, we will identify locations of IGA sequential CSR within mouse and human peyer's patches. In aim 2 we will define the role of germinal centers in shaping antigen-specific IGA production following mucosal immunization. We will define the isotype(s) of polyclonal memory b cells that are generated by mucosal immunization and will determine the role of the germinal center in memory formation and IGA memory recall responses. In aim 3 we will characterize the nature of CD4+ t cells that support antigen-specific IGA induction in the GUT. We will evaluate the contribution of TFH cells to IGA mutation and affinity-based selection, IGA+ memory generation, and sequential CSR. Finally, we will perform an unbiased characterization of t cells interacting with cognate antigen-specific b cells following GUT immunization. Once completed, this work will define how high-affinity IGA and long-lasting immune memory are generated in the GUT following immunization. This knowledge could be harnessed to help improve vaccine strategies and to advance interventions in intestinal diseases such as food allergy, celiac disease, and inflammatory bowel disease.