Intestinal B-cell isotype response in relation to local bacterial load: Evidence for immunoglobulin A subclass adaptation

Kett, K; Baklien, K; Bakken, A.; Kral, John G.; Fausa, O; Brandtzæg, Per

doi:10.1016/0016-5085(95)90389-5

Cited by 64 publications

(53 citation statements)

References 26 publications

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“…Dominant expression of IgA2, with higher resistance to bacterial proteases than IgA1, has been reported in the terminal ileum and is associated with higher bacterial load in more distal parts of the intestine (1,22). High amounts of TI bacterial carbohydrate antigens present in the gut may further support class switching to IgG2 and IgG4 as compared with systemic B cell compartments or IgG plasmablasts in the proximal small intestine with lower bacterial load (29).…”

Section: Discussionmentioning

confidence: 99%

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

Benckert¹,

Schmolka²,

Kreschel³

et al. 2011

J. Clin. Invest.

221

224

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Mucosal antibody responses play a major role in mediating homeostasis with the intestinal flora. It has been suggested that imbalance in the IgA + and IgG + intestinal B cell repertoire may be associated with the development of diseases such as inflammatory bowel disease. Despite this, little is known about the antibody specificity of human intestinal plasmablasts. Here, we have determined the reactivity profile of single isolated IgA + and IgG + plasmablasts from human terminal ileum using antibody cloning and in vitro expression. We found that approximately 25% of intestinal IgA and IgG plasmablast antibodies were polyreactive; the majority were antigen-specific. Antigen specificity was not only directed against enteropathogenic microbes but also against commensal microbes and self antigens. Regardless of their reactivity, all intestinal antibodies were somatically mutated and showed signs of antigen-mediated selection, suggesting that they developed from antigen-specific B cell responses. Together, our data indicate that antigen-specific immune responses to intestinal microbes are largely responsible for the maintenance of intestinal homeostasis and thus provide a basis for understanding the deregulated immune responses observed in patients with inflammatory bowel disease.

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Section: Discussionmentioning

confidence: 99%

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

Benckert¹,

Schmolka²,

Kreschel³

et al. 2011

J. Clin. Invest.

221

224

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“…23 ). IgA2 is particularly abundant at sites colonized by a large microbiota, including the distal intestinal tract and the urogenital tract [24][25][26] . Another difference between IgA1 and IgA2 relates to the fact that IgA1 has a longer hinge region than IgA2 (REF.…”

Section: Human Iga Subclassesmentioning

confidence: 99%

“…5) and further upregulate this expression on sensing bacteria via TLRs through a mechanism that involves DC activation by TSLP 26,99 . Together with IL-10, APRIL triggers IgA2 CSR in B cells 26 , suggesting that epithelial cells are central to the induction of IgA2 at mucosal sites colonized by a large microbiota, such as the colon 24,25 . At these sites, IgA2 may be more beneficial than IgA1, perhaps because IgA2 is more resistant than IgA1 to enzymatic digestion by bacterial proteases 25,28 .…”

Section: Role Of Epithelial Cells In Csr To C αmentioning

confidence: 99%

“…This feature renders IgA1 more susceptible to degradation by bacterial proteases that target the hinge region of IgA 23,28 . Furthermore, compared to IgA1 antibodies, IgA2 antibodies seem to have superior Fcα-mediated, mannose-dependent agglutinating properties against enteric microorganisms and exhibit more V H -mediated reactivity against LPS, a key component of Gram-negative bacteria residing in the distal gut 23,25 . …”

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confidence: 99%

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The regulation of IgA class switching

2008

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IgA class switching is the process whereby B cells acquire the expression of IgA, the most abundant antibody isotype in mucosal secretions. IgA class switching occurs via both T-celldependent and T-cell-independent pathways, and the antibody targets both pathogenic and commensal microorganisms. This Review describes recent advances indicating that innate immune recognition of microbial signatures at the epithelial-cell barrier is central to the selective induction of mucosal IgA class switching. In addition, the mechanisms of IgA class switching at follicular and extrafollicular sites within the mucosal environment are summarized. A better understanding of these mechanisms may help in the development of more effective mucosal vaccines.IgA has been selected throughout evolution to provide a first line of immune protection at mucosal surfaces -vulnerable frontline sites that are exposed to potentially harmful commensal, airborne, ingested and sexually transmitted agents. Growing evidence indicates that IgA uses a high-affinity binding system to neutralize microbial toxins and pathogens, and a low-affinity binding system to prevent commensal bacteria from breaching the mucosal surface 1 . This latter process is known as immune exclusion and has a fundamental role in the intestine, which is home to a number of commensal bacteria exceeding that of human cells by an estimated order of magnitude 2 .Remarkably, intestinal IgA achieves both immune protection and immune exclusion in a non-inflammatory manner, thereby promoting the establishment of a sustainable hostmicrobial mutualism 3 . The complex relationship between IgA and the intestinal microbiota is further exemplified by the fact that IgA responses are highly dependent on intestinal colonization by commensal microorganisms. Indeed, the number of IgA-secreting B cells is dramatically reduced in the intestine of germ-free animals and these cells are virtually absent in neonates before their exposure to bacteria 3 .In this Review, I summarize recent advances in our understanding of the function, regulation and geography of IgA class switching. In addition to analysing the signalling pathways underlying IgA class switching, I discuss new evidence indicating that commensal bacteria Competing interests statementThe author declares no competing financial interests. DATABASES Function of IgA class switchingAntibody diversification is essential for the immune system to mount protective humoral responses. B cells diversify their antibody repertoire through three main genetic alterations that occur in two distinct phases of B-cell development. In the antigen-independent phase, B-cell precursors lodged in the bone marrow generate antigen recognition diversity by assembling the exons that encode immunoglobulin heavy (H) and light (L) chain variable regions from individual variable (V), diversity (D) and joining (J) gene segments through V(D)J gene recombination 4 . This process is initiated by a lymphoid-cell-and sequencespecific RAG1 (recombination-activating gene 1...

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“…To evade the protective effect of S-IgA at the mucosal sites, some pathogenic bacteria (e.g., Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Neisseria gonorrhoeae) produce proteases which cleave the IgA1 molecule (31), leaving the IgA2 intact. The unequal distribution of IgA subclasses in different body fluids (5,13,28) and among IgA-secreting cells in the circulation (25) and mucosal and systemic lymphoid tissues (11,30) has been reported in several independent studies. The differential distribution of the two IgA subclasses in secretions has been shown to be accompanied by a similar distribution of IgA1-and IgA2-producing cells at those sites (11,30).…”

mentioning

confidence: 92%

Expression of Homing Receptors on IgA1 and IgA2 Plasmablasts in Blood Reflects Differential Distribution of IgA1 and IgA2 in Various Body Fluids

Pakkanen

Kantele

Moldoveanu

et al. 2010

Clin Vaccine Immunol

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Although secretory IgA is the most abundantly produced Ig isotype, the mechanisms underlying the differential distribution of IgA subclasses in various body fluids remain unclear. To explore these mechanisms, we examined the distribution of IgA subclasses, the influence of the nature and sites of encounters with antigens, and the correlation between IgA subclass distribution and homing potentials of circulating IgA plasmablasts. IgA1 predominated in serum, tears, nasal wash fluid, and saliva; the levels of IgA1 and IgA2 were comparable in vaginal wash fluid; and IgA2 predominated in intestinal lavage fluids. Seventy-one percent of circulating IgA plasmablasts secreted IgA1. The intestinal homing receptor (HR), ␣4␤7, was expressed more frequently on IgA2 than on IgA1 plasmablasts, with no differences in the expression of other HRs. IgA subclass distribution among circulating antigen-specific antibody-secreting cells (ASC) was dependent on the nature of the antigen: following vaccination with Salmonella enterica serovar Typhi, unconjugated pneumococcal polysaccharide, or Haemophilus influenzae polysaccharide-diphtheria toxoid conjugate, the proportions of specific IgA1 ASC were 74%, 47%, 56%, and 80%, respectively. HR expression depended on the route of administration: expression of HRs was different after oral than after parenteral vaccination, while no difference was seen between HR expression of antigen-specific IgA1 and IgA2 ASC induced via the same route. The key factors determining IgA subclass distribution in a given secretion are the nature of the antigens encountered at a particular site and the site-specific homing instructions given to lymphocytes at that site. These two factors are reflected as differences in the homing profiles of the total populations of circulating IgA1 and IgA2 plasmablasts.

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Intestinal B-cell isotype response in relation to local bacterial load: Evidence for immunoglobulin A subclass adaptation

Cited by 64 publications

References 26 publications

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

The majority of intestinal IgA+ and IgG+ plasmablasts in the human gut are antigen-specific

The regulation of IgA class switching

Expression of Homing Receptors on IgA1 and IgA2 Plasmablasts in Blood Reflects Differential Distribution of IgA1 and IgA2 in Various Body Fluids

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