Gastroenterology
Volume 137, Issue 5 , Pages 1570-1573, November 2009

Pathogen-Specific Antibody: Cause or Effect?

  • Tadakazu Hisamatsu
    • ,
  • Toshifumi Hibi

      Affiliations

    • Corresponding Author InformationReprint requests Address requests for reprints to: Toshifumi Hibi, MD, Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan

Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan

published online 28 September 2009.

Article Outline

 

See “An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice,” by Kobayashi K, Qiao S–W, Yoshida M, et al, on page 1746.

The serologic markers for inflammatory bowel disease (IBD) commonly used for diagnostic tools are anti-neutrophil cytoplasmic antibodies for ulcerative colitis (UC) and anti-Saccharomyces cerevisiae antibodies, which target mannose residues on mannan in the cell wall of the yeast S cerevisiae, for Crohn's disease (CD). Anti-neutrophil cytoplasmic antibodies has a prevalence of up to 85% among UC patients and 5%–28% among CD patients and healthy people, whereas anti-Saccharomyces cerevisiae antibodies has a prevalence of 48%–69% among CD patients and 15% among UC patients.1, 2 In addition, several recent studies have reported novel serologic markers for IBD, such as antibodies against outer membrane protein C of Escherichia coli, bacteria sequence (I2), bacterial flagellin (CBir), and antibodies against laminaribioside/chitobioside.3, 4, 5 These recent findings suggest strongly that an abnormal immune response to food antigens and enteric microorganisms occurs in IBD. However, it remains unclear whether these antibodies are direct pathogenetic factors in IBD or merely the results of an abnormal immune response.

CBir1 flagellin was identified in C3H/HeJBir animals that develop spontaneous colitis under normal conditions. Furthermore, C3H/HeJBir mice develop Th-1 responses and immunoglobulin (Ig)G2a antibodies to commensal bacterial antigens. Serologic screening identified several antigens in this model, and interestingly, the major class of antigens was bacterial flagellin. Clinically, anti-flagellin antibodies were also identified in approximately half of CD patients.6, 7

Of the several flagellins, CBir1 flagellin has been studied extensively. CBir1 flagellin-reactive Th-1 cells are able to induce colitis upon transfer to SCID mice.7 In human studies, the antibody to CBir1 flagellin is associated with complicated CD.4 These findings suggest that CBir1 flagellin, in particular, may have the potential for high immunogenicity.

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Neonatal Fc Receptor 

The neonatal Fc receptor (FcRn), also known as the Brambell receptor, was first identified in rodents in the 1970s as the receptor that transfers maternal IgGs from mother to the young via the neonatal intestine.8, 9, 10, 11, 12 FcRn comprises a heterodimer of 2 polypeptides of approximately 50 and 15 kDa, respectively.13, 14 It was reported that rat FcRn genes encode the 50-kDa polypeptide of FcRn, which is related to the major histocompatibility complex class I α-chains. The 15 kDa polypeptide was shown to be nonpolymorphic β2-microglobulin. Therefore, FcRn is recognized as a unique Fc receptor that belongs to the major histocompatibility complex class I family of proteins.15

FcRn binds to IgG at low pH (acidic), whereas it releases IgG at neutral pH.11, 16 This pH dependence of binding led to a proposed mechanism for IgG transcytosis in which FcRn binds to IgG at the slightly acidic pH of the neonatal gut lumen, transcytoses the bound IgG across the epithelium, and delivers them into the newborn's serum at pH 7.4.13, 14 FcRn also contributes to the maintenance of constant serum IgG levels in individuals.17, 18, 19 Consistent with this notion, mice, rat, and human FcRn are expressed in almost all tissues and cell lines.17, 20, 21

Thus, FcRn contributes to systemic and local immunity by recycling IgG and transporting IgG bidirectionally across epithelial cells. IgG is rescued from degradation in the intracellular lysosome by binding to FcRn and is subsequently transported to the plasma membrane. This mechanism of FcRn immunobiology helps to explain why IgG exhibits the longest half-life of all serum proteins.22 The pH-dependent binding to IgG allows FcRn to bind to IgG in the acidic endosomes and release IgG at the cell surface where it is at neutral pH. However, it remains unclear whether FcRn is expressed at the cell surface as it has not been detected there.23 In this regard, several exocytotic pathways have been suggested.9 FcRn binds not only IgG, but also to albumin and protects it from degradation in an intracellular catabolic state. Thus, FcRn also regulates albumin turnover.24, 25

Yoshida et al26 demonstrated that hFcRn can transport antigen-antigen–specific IgG complexes across epithelial cells using hFcRn-expressing MDCK cell lines. They also demonstrated that the antigen/IgG complexes transported by FcRn can stimulate CD4+ T cells through antigen presentation by antigen-presenting cells (APCs). Thus, these results suggest that FcRn plays a key role not only in protecting IgG from catabolic degradation, but also in sampling and transporting antigen/IgG complexes, and regulating the antigen-specific immune response.26 Furthermore, recent studies suggest that FcRn on innate immune cells, such as macrophages and dendritic cells (DCs), modulates also antigen presentation by APCs.27, 28

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Does Bacterial-Specific IgG Play a Pathogenetic Role in IBD? 

Kobayashi et al, in this issue of Gastroenterology, showed that anti-flagellin IgG contributed to the development of murine colitis.29 First, they observed an increase in serum anti-flagellin IgG after inducing dextran sulfate sodium (DSS)-induced colitis (at day 25).29 However, total serum IgG levels were unchanged, suggesting that the proportion of anti-flagellin IgG was increased in the total IgG. This result raises the question of whether increased anti-flagellin is just an effect of the immune response to an epithelial barrier break (and thus, no contribution to pathogenesis), whether it contributes to wound repair (beneficial effect), or whether it plays a pathogenic role in DSS colitis (a pathogenic factor).

To answer this question, anti-flagellin IgG was injected at day 0 in the DSS model. The mice with a high titer of anti-flagellin IgG at baseline exhibited exacerbated DSS-induced colitis.29 In addition, both wild-type (WT) and FcRn knockout (KO) mice were pre-immunized by flagellin before induction of DSS colitis. In FcRn KO mice, the increase in anti-flagellin IgG was relatively smaller than in immunized WT mice, but still higher than in nonimmunized WT mice. Thus, although immunized FcRn KO mice may produce sufficient amounts of anti-flagellin IgG, the inflammation was reduced. These data suggested anti-flagellin may play an important role in development of colitis in an FcRn-dependent manner. Furthermore, these data also raise another question of how FcRn is involved in anti-flagellin–induced colitis. Does lack of FcRn alter the antigen presentation on APCs? The authors focused on FcRn expression in APCs. To identify the role of FcRn in APCs, they established bone marrow chimeric mice. From the bone marrow chimeric mice studies, FcRn-dependent antigen presentation on APCs seems to be essential for development of anti-flagellin IgG-induced colitis.

Thus, the report by Kobayashi et al29 demonstrates the possibility that the anti-flagellin IgG/flagellin immune complex is a pathogenic factor for the development of IBD in mice through the FcRn system. However, there are still unanswered questions. How do DC recognize the anti-flagellin IgG/flagellin complex? Where does antigen presentation take place? Is the location of antigen presentation in mesenteric lymph nodes or in the lamina propria? Do those DCs that present antigens induce flagellin specific lamina propria CD4 T cells? (Analysis of the lamina propria CD4+ T cells in immunized models may be helpful in answering this question.) Identifying where DC recognize the complex may reveal local immune mechanisms of anti-bacteria IgG-related intestinal inflammation.

Whereas FcRn plays a role in the intracellular transport of immune complex, APCs express several Fc receptors on the surface (eg, FcγRII). The anti-flagellin IgG/flagellin immune complex may also be recognized by such cell-surface Fc receptors. Therefore, investigation of the interaction of surface Fc receptors with intracellular FcRn will be among the next tasks.

Flagellin is known as a ligand for Toll-like receptor 5 (TLR5) and also stimulates cell signaling via the TLR5 pathway. The connection with TLR5 is also unresolved. In particular, since the authors used Salmonella-derived flagellin in this report, when the immunogenicity of flagellin is considered, it is still controversial whether CBir1 flagellin is a particular flagellin that has high immunogenicity as discussed.30 In this regard, it is important to determine whether other antibacterial antibodies also have immunogenicity. In addition, the titer of anti-flagellin IgG of WT mice in the DSS-induced colitis model was increased at day 25 (recovery phase) and the titer level was relatively lower than that observed in immunized models. The results in this report may suggest that a break in the epithelial barrier (eg, with DSS) is necessary for induction of the anti-flagellin IgG/flagellin immune complex. Considering these points, a question remains on whether anti-flagellin IgG plays an important role in the initiation of colitis under normal conditions.

This study highlights the potential mechanisms of anti-bacterial antibodies in the pathogenesis of murine IBD and their relevance to serologic markers from a clinical perspective. If antibacterial antibodies contribute to the development or exacerbation of disease, titer levels of antibodies may reflect disease severity, prognosis, and response to therapies. The work of Kobayashi et al29 provides evidence for the pathogenetic role of anti-bacterial antibodies in IBD pathogenesis. The next several years will be interesting as researchers further dissect whether these mechanisms apply to human IBD (Figure 1).

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 Conflicts of interest The authors disclose no conflicts.

PII: S0016-5085(09)01669-2

doi:10.1053/j.gastro.2009.09.028

Refers to article:

  • Editorial Accompanies ArticleAdditional Online Content Available An FcRn-Dependent Role for Anti-flagellin Immunoglobulin G in Pathogenesis of Colitis in Mice , 06 August 2009

    Kanna Kobayashi, Shuo–Wang Qiao, Masaru Yoshida, Kristi Baker, Wayne I. Lencer, Richard S. Blumberg
    Gastroenterology November 2009 (Vol. 137, Issue 5, Pages 1746-1756.e1)

Gastroenterology
Volume 137, Issue 5 , Pages 1570-1573, November 2009

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