Introduction to IgA and Its Functions in the Gut
The gut serves as the largest interface for interaction between our body's indigenous microbes and the host immune system. Maintaining a distinct separation between microbes and adjacent tissues is crucial for sustaining a non-inflammatory homeostasis state in the human body. This symbiotic relationship between host and commensal bacteria is mediated by host-derived factors secreted on mucosal surfaces, such as mucus, antimicrobial peptides, and Immunoglobulin A (IgA). An overwhelming majority of mammals dedicate vast resources to IgA production; over 80% of human plasma cells secrete IgA and reside within the gut lamina propria. Immunoglobulin's protective immunity is mediated against gut pathogens, including viruses, bacteria, and toxins. Furthermore, IgA plays a significant role in maintaining gut homeostasis. Increased susceptibility to inflammatory bowel disease, celiac disease, and allergies has been observed in mice and humans with IgA secretion defects.
The Prevalence and Role of IgA Deficiency
IgA deficiency is relatively common in humans, with an incidence of 1/600 in Caucasians. Most subjects with IgA deficiency may display no discernible symptoms, exhibiting only a mild phenotype. Earlier studies suggested that to some extent, IgM can compensate for the deficiency of IgA. This concept has been further validated with and it now confirmed that IgA and less specific, IgM, can bind with the gut microbiota of healthy individuals. Furthermore, recent studies have shown that IgG usually has a higher binding affinity with gut bacteria than IgM. It has also been reported that the gut microbiota can escalate the serum levels of IgG, which in vitro also bind with gut bacteria. However, under the absence of IgA, the degree of in vivo interaction during bacterial coating by IgM and IgG and the activities of IgG, IgG1, IgG2, IgG3, or IgG4 subclasses remain unclear.
Significant Findings in IgA Deficiency Studies
A groundbreaking study published in Nature Communications employed quantitative and relative analysis methods to explore the nature and quantity of gut bacteria encapsulated by multiple immunoglobulins, including IgA, IgM, and IgG subtypes (IgG1-4), alongside 16S rRNA gene fragment sequencing. This research aimed to precisely describe the variations in barrier defense mechanisms among individuals with IgA deficiency, shedding light on why they often experience milder disease symptoms.
Variable Bacterial Coating in the Absence of IgA
A considerable quantity of fecal bacteria, approximately 7%, is coated with either single or multiple antibodies, with a overlap of 36% observed among IgA+ (any IgA coating) and IgA– (any IgM coating) participants. Roughly 32% of fecal bacteria have either single-layer or multiple-layer IgA coating but do not have IgM in the absence of IgA. In the lack of IgA, a similar proportion of the bacteria (32%) were coated only with either single or multiple IgM. These findings supported earlier research showing that the lack of IgA leads to an equivalent quantity of bacteria being coated only with single or multiple layers of IgM.
Fig 1. IgG assists IgM in coating of E. coli in the absence of IgA.1
The Potential Ability to Control Bacterial Invasion by Ig Coating
Scientists found that the majority of fecal bacteria, especially those from the Firmicutes phylum, were Gram-positive and were coated with only IgA or multiple IgA, but not single IgM or multiple IgM. On the other hand, in the absence of IgA, these same bacteria were uniquely coated with either single or multiple layers of IgM: a significant microbiome shift. This implies that humans likely have the potential to control the invasiveness of asymptomatic Escherichia coli via Ig coating.
In conclusion, this study revealed, in part, why individuals with a deficiency of IgA experience relatively mild disease symptoms and further highlighted the concerted contributions of IgA, IgM, and various subclasses of IgG to the complex, layered immune defense strategies operating within our guts. The findings could spur future research into the roles and therapeutic potential of these key immune factors in gut-associated diseases.
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Reference
- Eriksen, Carsten, et al. "IgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency." Nature Communications 14.1 (2023): 8124.
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