Knowledge about the regulation of the IgG subclass switching by Th cells is mainly based on studies in mice. However, the interactions are only partly understood. In a recent study Hjelholt et al. This implies that the mechanisms, which regulate the antibody production of the various IgG subclasses, are not fully understood. In the present study, we aimed to compare the IgG subclass profiles generated and maintained after infections or carriage by five microorganisms: parvovirus B19; the intracellular bacteria C.
Chlamydiae are small obligate intracellular bacteria with a unique biphasic life cycle Christiansen et al. The common human pathogenic species are C. Chlamydia trachomatis is a major cause of sexually transmitted diseases that may lead to scarring and occlusion of the fallopian tube causing ectopic pregnancy and tubal factor infertility TFI Beatty et al. Parvovirus B19 is a small nonenveloped single-stranded DNA virus infecting erythroid progenitor cells.
Mycoplasma are small wall-less bacteria belonging to the bacterial class Mollicutes. They are related to gram-positive bacteria and have small genomes. Mycoplasma pneumoniae can cause atypical pneumonia. It grows on the epithelial cells in the respiratory tract to which they adhere with their tip-like structure and destroys the ciliated cells Rottem, Streptococcus pneumoniae pneumococcus is a member of the mitis group within the genus Streptococcus.
Pneumococcus is not only an extracellular commensal of the upper respiratory tract of healthy individuals but also an important human pathogen. It causes many kinds of serious infections such as otitis media, sinusitis, pneumonia, sepsis, and meningitis. The immunoglobulin G IgG subclass antibodies specific to the five microorganisms were analyzed concurrently for each antigen in sera obtained from healthy Danish women Hjelholt et al.
We determined the IgG subclass profiles; thereby aiming at elucidating whether the route of infection, the infectious organism and the nature of the antigen would influence the IgG subclass distribution of the antibodies. Sera were obtained from Danish women undergoing IVF treatment.
This patient group was chosen, because a high prevalence of antibodies against C. None of the women had received pneumococcus vaccination. The patients were recruited to the project when they began their first IVF treatment.
The serum sample was taken in relation with the routine pregnancy test, which was performed 2 weeks after embryo transfer.
All women were healthy, at the time, the serum samples were taken, and they were not in antibiotic treatment Hjelholt et al. The different antigens used in the ELISA assays are located at the surface of the microorganisms and thus accessible to the immune system. Antibodies were determined by five ELISA methods using the same standards of subclass myeloma IgG and the same batches of subclass-specific, secondary antibodies in all assays.
Measurements of serum samples were performed with duplicates. The SPQ assays were preformed according to the instructions from the manufacture. The antigen is a purified lipopolysaccharide free native protein antigen. The antigen consists of a mixture of recombinant proteins. The analyses were preformed as SPQ assays see above. Briefly, the human serum samples were diluted 1 : 50 or 1 : in dilution Bac-dil buffer before use.
The subclass-specific secondary antibodies were added see above. In this way, the relative IgG levels were comparable between subclass values measured on the same antigen. Control wells two blanks containing Bac-dil buffer without serum sample were included on all plates.
The mean OD value and the standard deviation SD for the blank were calculated for each plate. Detection limit was defined as the mean OD value of the blank wells plus two times the standard deviation. The obtained OD values were plotted against the IgG concentration. The correlation coefficient R 2 was higher than 0. The data were analyzed using GraphPad Prism version 5. The mean and the standard error SEM were calculated from each series of analyses. Deming linear regression was used because it accounts for errors in both x and y observations.
The ELISA results demonstrate clear differences in the IgG subclass profiles of antibodies specific for the five kinds of antigen preparations used in our assays Fig. Bars represent median with interquartile range IQR. The mean levels were Relation between IgG subclass antibodies levels to five different microbial antigens. However, contrary to the findings for C. Figure 2b—d illustrate the predominance of IgG1 specific for these antigens. For C. IgG2 was the dominating subclass of the antibodies specific for C-polysaccharide of S.
IgG1 and IgG3 concentrations were low, and most of the serum samples contained undetectable levels of these two subclasses Table 1. IgG4 was not detectable in any of the serum samples. Deming linear regression analyses were performed to investigate the relation between the IgG1 and IgG3 antibody measurements for Chlamydia species, M. Lack of overlap of confidence intervals between regression lines of C. For both M. The humoral immune response, generated as a result of infection or carriage, is frequently characterized by presence of long-lasting antibodies in serum.
In the present study, we analyzed the subclass IgG response to common viral and bacterial antigens in serum samples from healthy Danish women undergoing IVF. The women had no infections, at the time, the serum sample was taken Hjelholt et al. Results from this study showed that in response to both the virus, the intra- and extracellular bacteria tested, IgG1 and IgG3 were produced, except for S.
This was expected, as this polysaccharide is a T-cell-independent type 2 antigen Yount et al. This kind of antigens is able to induce an antibody class shift from IgM to IgG2 without the assistance of T-cells. The IgG response to C. IgG4 was below detection level against all antigens, and because IgG4, together with IgE, is important in response to allergens, maybe fullfilling a down-regulatory, tolerance-inducing function Aalberse et al.
Human B cells are comprised of distinct subpopulations that differ in localization and function, although such cells are better characterized in rodents Swanson et al. Naive B cells have the potential to switch to production of any antibody isotype.
Cytokines secreted by activated Th cells are believed to take part in the redirection of this isotype switch Stavnezer et al. In the present study, we did not observe a distinction in the production of IgG subclasses dependent on whether the pathogen was intra- or extracellular, a bacterium, or a virus even though the ratio between IgG1 and IgG3 differed.
This suggests that the Th-cell distinction is not exclusively dependent on the type of pathogen. The difference in IgG subclass production in response to C. This suggests that other factors besides the characteristics of the infectious organism are crucial in the determination of the IgG profile.
Because parvovirus B19, C. Other studies have suggested a difference in Th response depending on the infectious route. When infecting mice intravenously with Listeria monocytogenes, Pepper et al. This may subsequently influence the subclass of IgG antibodies produced. IgA is the predominant antibody in mucous secretions such as saliva, tears, milk and intestinal juice. Like IgM, the multimeric form of IgA contains a tail piece at the carboxy terminus and is held together by the J chain.
The secretory component is a 75 kDa polypeptide chain synthesised by epithelial cells of the gut for linkage to the dimeric form of IgA. As the name implies the secretory component facilitates IgA transport across epithelial cells but is also involved in protecting IgA secreted into the lumen of the gut from proteolytic digestion.
IgD has the same basic structure as IgG but with an extended hinge region which is very susceptible to proteolytic digestion. The precise function of this class of antibody is still unknown. IgE is very scarce in the serum but is found on the basophils and mast-cells of all individuals 1. In a similar manner to IgM, IgE has two additional constant domains in place of the hinge region.
With this role in mucosal immunity, it complements sIgA in immunoregulatory function as reviewed in Ref. As IgG can transport fully folded and functional proteins across epithelial barriers, this offers new possibilities for FcRn as an endogenous receptor to transport Fc-Fusion proteins or vaccine antigens across otherwise impermeable epithelial surfaces On mucosal cells, FcRn has been found to transport IgG and be involved in antigen sampling , , , and its expression on phagocytic cells , has recently been found to enhance phagocytosis capacity of IgG-opsonized particles , On antigen-presenting cells, this ingestion of IgG-complexes can lead to enhanced presentation — Thus, immunoglobulin activities including extended half-life, transport to young, and antigen sampling seems to be orchestrated through a single receptor, the MHC-class I-like FcRn.
Although FcRL5 seems broadly expressed on B-cells populations , FcRL4 is only expressed on subepithelial tissue B-cells reportedly of mucosal origin, suggesting that perhaps this receptor is involved in negative feedback inhibition through antigen-specific IgG and IgA, respectively.
Tripartite motif-containing protein 21 TRIM21 is a cytosolic protein expressed in almost all cell types but highly expressed in immune cells. TRIM21 previously known as an autoantigen involved in several autoimmune diseases, e.
Later, it was demonstrated that TRIM21 functioned as an immunological sensor, targeting IgG-opsonized virus and bacteria for antibody-dependent intracellular neutralization by the ubiquitin-dependant proteosome — The detection of antibody opsonized virus by this receptor activates, requires proteasome and the ATPase and unfoldase VCP , The unique localization of this receptor in the cytoplasm leaves many unanswered questions but simultaneously answering many.
The relative importance of this system is still unknown during secondary infections, but may perhaps be relatively more important at locations where complement and the myeloid system are less prominently present, e. The cytotoxic activity of sialylated IgG has been described to be reduced in mice However, the precise mechanisms of this interaction are unknown, and still await confirmation — particularly in the human setting, but also in mice as some of the methods used to enrich IVIG for SA were found to predominantly — if not exclusively — enrich for Fab-associated SA 58 , However, recently an alternative receptor, the dendritic cell immunoreceptor DCIR has been put forward as an alternative candidate mediating the anti-inflammatory effect of silalylated-IgG, inducing upregulation of T regulatory cells, and minimizing Ig-complex-mediated airway hyperresponsiveness Immunoglobulin G-mediated responses diverge and depend largely on the type of secondary immune responses, which in turn depend on the type of antigen.
This directs the immune response to a specific IgG subclass or subclasses — the function of which differs greatly between them. Besides this variation, the IgG profile of a given individual determined by their inherited allotypes can potentially influence the clinical manifestation of the immune response, which ultimately differs between individuals and populations.
An even greater level of complexity is added by the profound variation seen in the glycosylation of the Fc tail, affecting binding to various receptors — the nature of which we are just beginning to understand.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. National Center for Biotechnology Information , U. Journal List Front Immunol v. Front Immunol. Published online Oct Author information Article notes Copyright and License information Disclaimer.
This article was submitted to Immunotherapies and Vaccines, a section of the journal Frontiers in Immunology. Received Aug 31; Accepted Oct 6. The use, distribution or reproduction in other forums is permitted, provided the original author s or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
This article has been cited by other articles in PMC. Abstract Of the five immunoglobulin isotypes, immunoglobulin G IgG is most abundant in human serum. Keywords: immunoglobulin G, IgG, Fc receptors, neonatal Fc receptor, glycosylation, polymorphism, genetic. Table 1 Properties of human IgG subclasses. Open in a separate window.
IgG antibody responses The route by which an antigen enters our body and its chemical composition steers the secondary immune reaction into preferential patterns of class switching. IgG1 Antibody responses to soluble protein antigens and membrane proteins primarily induce IgG1, but are accompanied with lower levels of the other subclasses, mostly IgG3 IgG4 9.
IgG2 Immunoglobulin G-antibody responses to bacterial capsular polysaccharide antigens can be almost completely restricted to IgG2 9 , 11 — 13 , and IgG2 deficiency may result in the virtual absence of IgG anti-carbohydrate antibodies 14 , although these responses can also be compensated for by enhanced levels of other IgG subclasses, in particularly by elevated IgG1 and IgG3 levels IgG3 IgG3 antibodies are particularly effective in the induction of effector functions.
Figure 1. Figure 2. Structural Variation in the Hinge Region The hinge region forms a flexible linker between the Fab arms and the Fc part. Figure 3. Glycosylation Immunoglobulin G contains a conserved glycan at position N of the heavy chains. Bisection Slight changes in bisection have been detected for some antigen-specific IgG responses 54 , , , Galactosylation To our knowledge, no data have been published to date on the influence of galactosylation on the level of antigen-specific IgG.
Effector Mechanisms Binding to effector molecules Antibodies link the adaptive immune system with the effector mechanisms of the innate immune system. Concluding Remarks Immunoglobulin G-mediated responses diverge and depend largely on the type of secondary immune responses, which in turn depend on the type of antigen. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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