Inflammatory modalities shape the IgA repertoire via stochastic processes

Area of Science:

• Immunology
• Gastroenterology
• Microbiology

Background:

• Intestinal mucosal immunity depends on immunoglobulin A (IgA).
• Homeostatic IgA levels are abundant in the gut.
• Inflammation can further amplify IgA production.

Purpose of the Study:

• To characterize the inducible B cell response during intestinal inflammation (colitis).
• To analyze the properties of IgA produced by adaptive and innate B cell subsets during inflammation.
• To investigate the specificity and reactivity of inflammation-induced IgA.

Main Methods:

• Characterization of B cell responses during experimental colitis.
• Analysis of IgA production by adaptive and innate B cell subsets.
• Assessment of IgA specificity, affinity maturation, and cross-reactivity.

Main Results:

• Massive clonal expansion of specific B cell lineages occurred during colitis, amplifying IgA plasma cells.
• Inflammation-induced IgA showed Fab-dependent recognition of commensal taxa and cross-reactivity to autoantigens.
• The majority of inflammation-induced IgA was non-reactive to microbiota, arising from germline-encoded bystander B cells.
• Significant, unpredictable variation in microbiota- and auto-reactive IgA prevalence was observed among individual mice.

Conclusions:

• While mucosal B cells can produce microbiota-targeting IgA, inflammation drives expansion of non-specific IgA-producing B cells.
• Stochastic selection of B cell lineages in the inflammatory environment leads to unpredictable IgA reactivity.
• This random B cell selection during inflammation may have unforeseen pathophysiological consequences.