J Chain Research Articles

Amyloid‐like IgM deposition neuropathy: a distinct clinico‐pathologic and proteomic profiled disorder

Some patients with immunoglobulin paraproteinemic neuropathy have intra-nerve deposits that morphologically mimick amyloid, but do no stain with Congo red. Patients with amyloid-like deposits were identified. The nerve amyloid-like aggregates were studied by laser microdissection and dual mass spectrometry. Three male patients, all with IgM gammopathy, and neuropathy were identified. Follow-up, disease duration was 5, 19, and 7 years, respectively. All had progressive asymmetric sensory-onset distal axonal polyneuropathy with late motor involvement. Autonomic symptoms occurred in only one after 13 years of symptoms. None had clinical cardio-renal involvement. One had skin papules with dermal amyloid-like deposits. Endoneurial amyloid-like deposits had granulo-fibrillar ultrastructure. Mass spectrometry of laser-dissected deposits identified IgM pentameric macroglobulin (heavy, light, and joining chains) without amyloid-associated proteins including absent apolipoprotein E and serum amyloid P-component. Amyloid-like neuropathy has distinct clinical, pathologic, and proteomic features which expand the spectrum of IgM neuropathies. Patients have favorable survival, relative absence of autonomic features, and distinct proteomic profiles of the infiltrative protein in nerve.

Establishment of Recombinant Hybrid‐IgG / IgA Immunoglobulin Specific for Shiga Toxin

Shiga toxin 1 produced by enterohaemorrhagic Escherichia coli is an AB(5) toxin that is involved in the life-threatening haemolytic-uraemic syndrome. The B subunits (Stx1B) are cell-binding subunits. We previously established mouse hybridoma cell line producing IgA and IgG monoclonal antibodies (mAbs) against Stx1B. Here, we cloned cDNAs encoding each of the heavy, light and joining (J) chains from the hybridoma cell lines by means of the 5' rapid amplification of cDNA ends (RACE) PCR method. Upon assignment of the variable regions of the heavy and light chains to known germline sequences, we found substantial somatic hypermutation in the complementarity-determining regions in both the IgA and IgG mAbs. We also established a hybrid-IgG/IgA heavy chain having variable regions of the IgG mAb by means of recombinant PCR methods. Upon transient expression of the hybrid-IgG/IgA heavy, IgG-associated light and J chains in COS-1 cells, the translated dimeric hybrid-IgG/IgA bound to immobilized Stx1B, as revealed on ELISA. The production of dimeric hybrid-IgG/IgA was revealed on immunoblot analysis. The dimeric hybrid-IgG/IgA inhibited the binding of digoxigenin-conjugated Stx1B to natural ligands (CD77) displayed on Burkitt's lymphoma cell line Ramos. These results indicate that the replacement of variable regions resulted in the production of more useful recombinant dimeric IgA against Stx1B.

Screening biomarkers in bone marrow supernatant of multiple myeloma by 2-DE and MALDI-TOF-MS

Objective To analyze the differentially expressed proteins in bone marrow supernatants of multiple myeloma patients by using 2-DE and MALDI-TOF-MS,and search for the special protein markers for studying the mechanism of the development and diagnosis or differential diagnosis of multiple myeloma.Methods The bone marrow supernatant samples of fourteen multiple myeloma patients,five other hematologic malignancies and five normal controls were collected.After removing albumin and IgG,the proteins in the supernatants were separated by 2-DE.Three groups images were analyzed and compared by Imagemnster 2D platinum 5.0 analysis software.Differentially expressed proteins were selected if the protein spots intensity showed more than 3 fold increase or decrease among different groups.The identities of the differentially expressed proteins with good repeatibility were determined by PMF based on by MALDI-TOF-MS or MALDI-TOF-MS/MS and NCBInr database search.Results 2-DE maps of bone marrow supernatants of the three groups could be analyzed and compared by image analysis of software.Forty-seven and fifty-eight differentially expressed protein spots were detected in multiple myeloma samples compared with normal controls and other hematologic malignancies samples,respectively.Forty-one reproducible spots were analyzed and identified by mass spectrum.Compared with other hematologic malignancies and normal controls,five up-expressed proteins and three down-expressed proteins were identified in multiple myeloma samples.They includes immunoglobulin J chain κ and λ light chain,provirus ancestral Gag polyprotein,mature oxy-cope catalytic antibody with hapten for up-expressed proteins,and hemoglobin,haptoglobin Hp2,zinc-alPha-2-glycoprotein for down-expressed proteins.These differentially expressed proteins reflect the features of muhiple myeloma,and relate to the development,progression and therapy of multiple myeloma.Conclusions Eight differentially expressed proteins in bone marrow supernatants of multiple myeloma are identified by using 2-DE and MALDI-TOF-MS.These differentially expressed proteins could be useful in studying the mechanism of the development and progression of multiple myeloma,and in developing diagnosis and differential diagnosis of multiple myeloma. Key words: Multiple myeloma; Electrophoresis, gel, two-dimensional; Spectrometry, mass,matrix-assisted laser desorption-ionization; Biological markers

Immunoglobulin joining (J) chain and its expression in the Chinese soft-shelled turtle ( Pelodiscus sinensis)

The immunoglobulin (Ig) joining (J) chain plays an important role in the formation of polymeric Igs and their transport into secretions. In the present study, the cDNA sequence of J chain has been cloned from the Chinese soft-shelled turtle ( Pelodiscus sinensis) by reverse transcription (RT)-PCR and rapid amplification of cDNA ends (RACE). The cDNA sequence is 2347 bp in length and contains an open reading frame of 480 bp encoding 160 aa including the signal sequence. The deduced amino acid sequence has a high degree of homology with that of an already reported turtle J chain (80.7%), and of chicken (71.3%). By using real-time quantitative RT-PCR analysis, a significant up-regulation of J-chain transcripts was observed in spleen, kidney and blood of turtles injected with inactivated Aeromonas hydrophila, indicating the immune role of J chain in response to bacterial infection.

Cover Picture: Eur. J. Immunol. 4/09

AbstractThe cover image, provided by Ghumra et al. (pp. 1147–1156), shows two views of a molecular model of human dimeric IgA1 revealing residues predicted to be critical for interaction with human Fca/mR, a receptor with specificity for the Fc regions of IgA and IgM. The IgA heavy chains (tailpieces omitted) are shown in yellow, and the light chains in blue. The heavy chain residues proline 440 to phenylalanine 443 on the Ca3 domain of the IgA Fc region, implicated in hFca/mR interaction, are shown as red spheres. The J (joining) chain of the dimeric IgA is not included in the model, but the white dotted line in the lower view indicates a possible position.

In this issue

In this issue

The Nonplanar Secretory IgA2 and Near Planar Secretory IgA1 Solution Structures Rationalize Their Different Mucosal Immune Responses

Secretory IgA (SIgA) is the most prevalent human antibody and is central to mucosal immunity. It exists as two subclasses, SIgA1 and SIgA2, where SIgA2 has a shorter hinge joining the Fab and Fc regions. Both forms of SIgA are predominantly dimeric and contain an additional protein called the secretory component (SC) that is attached during the secretory process and is believed to protect SIgA in harsh mucosal conditions. Here we locate the five SC domains relative to dimeric IgA2 within SIgA2 using constrained scattering modeling. The x-ray and sedimentation parameters showed that SIgA2 has an extended solution structure. The constrained modeling of SIgA2 was initiated using two IgA2 monomers that were positioned according to our best fit solution structure for dimeric IgA1. SC was best located along the convex edge of the Fc-Fc region. The best fit models showed that SIgA2 is significantly nonplanar in its structure, in distinction to our previous near planar SIgA1 structure. Both the shorter IgA2 hinges and the presence of SC appear to displace the four Fab regions out of the Fc plane in SIgA2. This may explain the noncovalent binding of SC in some SIgA2 molecules. This nonplanar structure is predicted to result in specific immune properties for SIgA2 and SIgA1. It may explain differences observed between the SIgA1 and SIgA2 subclasses in terms of their interactions with antigens, susceptibility to proteases, effects on receptors, and distribution in different tissues. The different structures account for the prevalence of both forms in mucosal secretions.

A subset of dendritic cells express joining chain (J‐chain) protein

Joining chain (J-chain) is well known as an integrated component of dimeric immunoglobulin A (IgA) and pentameric IgM. We show here that the J-chain protein is also expressed in a subset of CD11c+ dendritic cells (DC) in C57BL/6 mice. J-chain knockout mice (J-/- mice) had a reduced fraction of CD4-/CD8alpha+ and mPDCA-1+ DC in the spleen. J-/- mice also had reduced levels of RNA for the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in the spleen. Furthermore, in lymph nodes from C57BL/6 mice the majority of J-chain-expressing CD11c+ cells also expressed IDO, while the number of IDO-expressing cells in lymph nodes and the amount of IDO protein in splenic CD11c+ cells were reduced in J-/- mice. Also, J-/- mice had a lower ratio of kynurenine/tryptophan in serum compared to C57BL/6 mice, indicating a lower overall IDO activity in J-/- mice. We also show that J-/- mice are less susceptible to tolerance induction than C57BL/6 mice. In conclusion, our data show that J-chain protein is expressed outside the B-cell compartment in a subset of immunoregulatory DC that are compromised in animals that cannot express J-chain.

Recombinant Chimeric IgA1 and IgA2 Antibodies for Tumor Immunotherapy.

The therapeutic potential of human IgA antibodies has hardly been explored, although IgA is the most abundantly produced antibody isotype in humans. Here, we describe the generation and functional characterization of human/mouse chimeric IgA antibodies against the epidermal growth factor receptor (EGF-R), which is a validated target antigen for tumor immunotherapy. Human IgG1, IgA1 and IgA2 variants of the C225 antibody were produced in CHO-K1 transfectomas using serum-free, non-adherent culture conditions. Productivity rates of selected IgA producing clones were approximately 5 pg/cell/day. A two-step purification procedure consisting of thiophilic agarose columns followed by gel electrophoresis on Superdex 200 yielded highly purified monomeric IgA antibodies, which were stable at 4° C. Silver staining and Western blots with human kappa-light- and human α-heavy chain antibodies confirmed the purity and correct assemby of IgA1 and IgA2 antibodies. Co-transfection of a His-tagged joining (J) chain significantly increased the amount of dimeric IgA antibodies, which were detected by anti-His antibodies. IgG1 and monomeric IgA antibodies demonstrated similar binding to EGF-R expressing A431 tumor cells (EC50 approx. 10 μg/ml) and to EGF-R transfectants. Furthermore, IgA1 and IgA2, but not IgG1 demonstrated binding to FcαRI (CD89)- transfected cells. All three isotypes were similarly effective in recruiting F(ab')- mediated killing mechanisms such as blockade of EGF binding, inhibiting EGF-R phosphorylation, and mediating growth inhibition of EGF-R expressing cells. All three isotypes did not activate complement- mediated killing. Human IgG1 effectively triggered MNC- mediated ADCC, but activated PMN only weakly. Importantly, both human IgA isotypes were significantly more effective than IgG1 in recruiting neutrophils for ADCC (EC50 approx. 0.25 μg/ml), and triggered ADCC at effector to target cell ratios as low as 5:1. Since neutrophils constitute the most abundant effector cell population in human blood, IgA antibodies triggered higher levels of tumor cell killing in whole blood assays than human IgG1 antibodies - particularly when blood from G-CSF- primed donors was compared to healthy donor blood. Together, these data suggest that recombinant human IgA antibodies can be produced in reasonable amounts, and that they may constitute promising reagents for immunotherapy.

Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma

L612, a human IgM monoclonal antibody produced by an EBV-transformed human B-cell line, binds to ganglioside GM3 and kills GM3-positive human melanoma cells in the presence of complement. It has been shown to be effective in some patients with late-stage melanoma. L612 consists of hexameric IgM (about 20%), pentameric IgM (about 74%), and other minor IgM molecules. Because hexameric IgM activates complement more effectively than pentameric IgM, we developed and evaluated a hexamer-dominant recombinant IgM for clinical applications. Chinese hamster ovary (CHO) cells were transfected with heavy- and light-chain genes of L612, with or without the joining-chain gene. Antitumor effects of the recombinant IgM secreted from CHO cells were evaluated in vitro and in vivo. Recombinant IgM secreted from CHO cells without the joining chain (designated CA19) was approximately 80% hexameric, whereas recombinant IgM from CHO cells transfected with heavy-, light-, and joining-chain genes (designated CJ45) was about 90% pentameric. Both CA19 and CJ45 recombinant IgMs caused complement-dependent cytotoxicity against human and mouse melanoma cell lines, but the amount of CA19 required for 50% specific cytotoxicity was 5 to 10 times smaller. I.v. injection of CA19 compared with CJ45 or native L612 elicited more profound antitumor activity in nude rats bearing a GM3-positive mouse melanoma xenograft. A hexamer-dominant human IgM against GM3 may provide a more potent treatment option for patients with GM3-positive melanoma.

Secretory Antibody Formation: Conserved Binding Interactions between J Chain and Polymeric Ig Receptor from Humans and Amphibians

Abs of the secretory Ig (SIg) system reinforce numerous innate defense mechanisms to protect the mucosal surfaces against microbial penetration. SIgs are generated by a unique cooperation between two distinct cell types: plasma cells that produce polymers of IgA or IgM (collectively called pIgs) and polymeric Ig receptor (pIgR)-expressing secretory epithelial cells that mediate export of the pIgs to the lumen. Apical delivery of SIgs occurs by cleavage of the pIgR to release its extracellular part as a pIg-bound secretory component, whereas free secretory components are derived from an unoccupied receptor. The joining chain (J chain) is crucial in pIg/SIg formation because it serves to polymerize Igs and endows them with a binding site for the pIgR. In this study, we show that the J chain from divergent tetrapods including mammals, birds, and amphibians efficiently induced polymerization of human IgA, whereas the J chain from nurse shark (a lower vertebrate) did not. Correctly assembled polymers showed high affinity to human pIgR. Sequence analysis of the J chain identified two regions, conserved only in tetrapods, which by mutational analysis were found essential for pIgA-pIgR complexing. Furthermore, we isolated and characterized pIgR from the amphibian Xenopus laevis and demonstrated that its pIg binding domain showed high affinity to human pIgA. These results showed that the functional site of interaction between pIgR, J chain and Ig H chains is conserved in these species and suggests that SIgs originated in an ancestor common to tetrapods.

Recombinant human J-chain: Fix the protein aggregations and yield maximize

Polymeric immunoglobulin (dimeric IgA and pentameric IgM) molecules can assembly by using the immunoglobulin J (joining) chain and across the epithelial cell layers. Based on its amino acid and gene sequences data, disulfide bond (2 bonds) assignment secondary structure predictions, and chemical properties, a model for J-chain folding has been proposed. However, the crystal structure of the J-chain protein is still far from obtained, because the J-chain expression and its protein downstream has a permanent aggregation problems, due to its two free thiol groups. Our work focused on the chemical blocking of free cysteines-SH or to mutate these cysteines into serine residues. The chemical blocking yielded partially soluble proteins with new structures (carboxyamidomethyl cysteine and carboxyamidomethyl methionine) at cysteine and methionine residues. While mutate the cysteines into serine has been yielded a complete soluble (11.5 mg/l) J-chain protein which migrate (SDS-PAGE) at 27 KDa. We were used pET22b expression vector and E. coli BL21 (DE3) to produce the J-chain protein. For maximization the production yield of j-chain foreign protein, the batch culture was developed. We described the scaling-up production in term of kinetic behavior to the recombinant E.coli and optimization of cultivation parameters in 3-L bench-top bioreactor. The process was automated through a computer aided data bioprocessing system AFS-BioCommand multi-process management program to regulate the cell growth rate, temperature, pH and agitation speed based on dissolved oxygen. The results showed an obvious increasing in biomass by 5.98 g/L after about 27 h [corrected]

Analysis of Antigen‐Specific and Naturally Occurring IgM and IgA Steady‐State Levels in J‐Chain Negative C57BL/6 Mice

Naturally occurring IgM and IgA levels are remarkably stable between different individuals. In mice lacking joining chain (J-chain), the steady-state levels of IgM are reduced, while IgA levels are elevated. We have here analysed the IgM and IgA responses as well as the regulation of naturally occurring antibodies in mice that delete all J-chain expressing B cells (JDTA mice) and have been back-crossed to C57BL/6 mice. The IgM response to a T-cell-dependent antigen was reduced in JDTA mice but still easily detectable. In contrast, a very pronounced primary IgA response could be detected in JDTA mice while wild type controls showed no detectable primary IgA response. With regard to naturally occurring antibodies, bone marrow chimeras between JDTA and control C57BL/6 mice had a donor cell phenotype with regard to serum IgM and IgA. Mixed bone marrow chimeras had an intermediate phenotype, indicating that the naturally occurring antibody IgM and IgA levels are B-cell autonomous and not subjected to feed-back control. This was confirmed by transfer of the dominant naturally occurring IgM/IgA phenotype to the recipient by peritoneal exudate cells.

Two secretory immune systems (mucosal and barrier) in human intrauterine development, normal and pathological (Review)

The role of protein components of the secretory immune system (SIS), such as the polymeric immunoglobulin receptor/secretory component (pIgR/SC), immunoglobulins (Igs) and joining (J) chain, in human intrauterine development was reviewed. These components are already present in 3.5- to 4-week-old embryos, and found in all tissues and organs of epithelial origin. The SIS is made up of two parts: the SIS of mucous membranes and their derivatives (mucosal or secretory immune system), and the SIS of barrier structures (barrier immune system). During organogenesis, SC disappears from the cells of organs that lose their exocrine Ig-secretion function, such as the hypophysis, pancreatic islands and adrenal glands. In cells and tissues of mesenchymal origin, SC is absent from the start, i.e. during their initial development. As examples of the barrier immune system, blood-tissue and tissue-tissue barriers, such as the chorion of the placenta, the epithelium of the choroid plexuses in the brain, as well as other barrier structures to Ig transfer were considered. Besides the SC and J chain, Fc receptors, cellular and tissue structures participate in this process. Three stages were described in Ig transfer: i) passing from the maternal blood into intervillous spaces and the trophoblast, ii) shifting in the intravillous stroma and its cells, and iii) excretion into embryonic (fetal) blood through the endothelium of the trophoblastic villous capillaries. Igs of maternal origin, mainly IgG and least abundant IgA, pass through the placental barrier in healthy embryos. Following a massive antigenic attack, the increased exocrine secretion of IgG, IgA, and IgM to a lesser extent, are already seen in embryos, reflecting increased functional activity of the SIS. Thus, in human intrauterine development, the SIS is a very early immune defensive system, which presents and acts before the appearance of the common lymphoid system.

Secretory immune system in human embryonic and fetal development: Joining chain and immunoglobulin transport (Review)

The role of joining (J) chain, one of the protein components of the secretory immune system (SIS), in the immune reactions of the human embryo and fetus was analyzed on the basis of data from the literature and our previous studies. All organs and structures, including extra-corporeal ones, of 18 embryos (4-8 weeks of development) and 45 fetuses (9-38 weeks) were studied using methods of pathomorphology, immunohistochemistry and morphometry. This approach enabled us to analyze the problem in the whole organism throughout its embryonic and fetal development. J chain, as well as polymeric immunoglobulin (Ig) receptor-secretory component (pIgR/SC) and Igs, are already widely distributed in 4-week-old embryos before the appearance of the common immune system. The whole complex of protein components of the SIS was seen in mucous layers, and in blood-tissue and tissue-tissue barrier structures. Therefore, we can consider two parts of the SIS: mucosal and barrier. Already in embryos, an increase in the functional activity of the SIS following massive antigenic attack in cases of acute chorioamnionitis reflects the increased exocrine secretion of Igs. The J chain appears to participate in the endocytosis but not exocytosis of Igs. J chain and Igs, but not pIgR/SC, were present in cells of the heart, endocrine glands, gonads and some other organs. The exocrine secretion of Igs, the main function of the SIS, is absent in these organs, and, they are therefore, not considered part of the SIS.

Synergistic interaction of two independent genetic loci causes extreme elevation of serum IgA in mice.

Understanding the molecular regulation of immunoglobulin A (IgA) expression is important as it plays an essential role in the first-line defence through mucosal secretions. Using inbred mouse strains, we identified two independent and dominant acting genetic loci that synergistically cause a 40-fold upregulation in serum IgA levels when introduced into the murine strain C57Bl/6J (B6). The first locus on chromosome 12 appears to be mainly responsible for the natural four-fold higher IgA levels in C3HeB/FeJ (C3H) compared to B6 mice. A second independent, chemically induced mutation on chromosome 5 caused a two-fold elevation when transferred from C3H into B6 mice. Both loci in concert effect a 40-fold elevation against the B6 genetic background. We determined the chromosomal localization of the two loci simultaneously by a one-step mapping process. The chemically induced mutation was identified within the immunoglobulin joining chain (IgJ) gene on chromosome 5. The major serum IgA modifier between the C3H and B6 was located on chromosome 12. This modifier region was mapped to a 350 kb region containing several immunoglobulin heavy-chain genes and the Ig alpha germline switch gene. We speculate that by interfering with both IgA expression and distribution, synergistic regulation of IgA is achieved.

Phylogenetic relationships in Carex , subgenus Vignea (Cyperaceae), based on ITS sequences

To evaluate the sectional classification in Carex, subgenus Vignea, the ITS region of 58 species of 20 sections was analyzed with Neighbor Joining (NJ) and Markov chain Monte Carlo (MCMC) methods. Sections Dioicae, Physodeae and Ovales are found to be monophyletic, with C. bohemica well integrated in the section Ovales. Section Heleonastes turns out to be monophyletic, if C. canescens is treated separately in section Canescentes. Section Elongatae is monophyletic, but C. remota is placed in section Remotae and C. bromoides in section Deweyanae. In both analyses, six representatives of section Arenariae cluster together in a terminal group, whereas C. disticha, C. repens and C. siccata form a basal cluster. C. maritima, as the only member of section Incurvae, shares this basal position. C. chordorrhiza is ascribed to section Chordorrhizeae and not ascribed to the paraphyletic section Divisae. C. vulpina and C. otrubae are assigned to section Vulpinae and separated from the heterogeneous section Stenorhynchae. The other members of sections Divisae, Muehlenbergianae, Multiflorae and Stenorhynchae are scattered throughout the trees. The representatives of section Foetidae are dispersed in both analyses, section Paniculatae appears to be non-monophyletic in the molecular results as well. The subgenus appears subdivided in at least four larger subgroups in all analyses. Whereas these subgroups are strongly supported, the relationships between these subgroups remain only poorly resolved.

Carex , subgenus Carex (Cyperaceae) ? A phylogenetic approach using ITS sequences

To evaluate the sectional classification in Carex, subgenus Carex, the ITS region of 117 species belonging to 32 sections was analyzed with Neighbor Joining (NJ) and Markov chain Monte Carlo (MCMC) methods. In our analyses (1) species of subgenus Indocarex appear as a statistically well supported group within subgenus Carex. (2) The representatives of sections Vesicariae, Hirtae, Pseudocypereae, Ceratocystis, Spirostachyae, Bicolores, Paniceae, Trachychlaenae, Scirpinae, Atratae and Albae group in statistically supported clades with higher support in MCMC than in NJ. (3) C. rariflora clusters with representatives of section Limosae, however only weakly supported. (4) Taxa of section Phacocystis are divided in two statistically supported subclusters that are closely related to a core group of section Hymenochlaenae. (5) Species of sections Montanae, Pachystylae, Digitatae, Phacocystis, Rhomboidales, Careyanae and Frigidae are segregated into two or more clusters each. (6) Five species of section Frigidae cluster together, whereas the seven others are in scattered positions. Based on these results, delimitation of sections is discussed.

Secretory immune system in human intrauterine development: Immunopathomorphological analysis of the role of secretory component (pIgR/SC) in immunoglobulin transport (Review)

Several proteins, such as polymeric immunoglobulin (Ig) receptor/secretory component (pIgR/SC), immunoglobulins (Igs) and joining (J) chain, and cellular components of the secretory immune system (SIS) of the human embryo and fetus were analyzed and compared with reviewed information concerning SIS organization and function. All organs and structures, including extracorporeal ones, of 18 embryos (4-8 weeks of development) and 45 fetuses (9-38 weeks) were studied using methods of pathomorphology, immunohistochemistry and morphometry. This approach enabled us to analyze the problem in the whole organism during its entire development. SC, Igs and J chain were already widely distributed in 4-week-old embryos and were later seen in the mucosa and glands of the digestive, respiratory and urogenital tracts, ovaries, testis, endocrine glands, extracorporeal tissues, blood-brain and other blood-organ barrier structures, as well as in serous membranes. The presence of protein transport and later of cellular components suggests an active role for SIS not only in mucous membranes, but also in blood-tissue barriers. Loss of morphological contact between epithelial structures and mucous membranes during organogenesis of some endocrine organs (hypophysis, pancreatic islets, etc.) is followed by the disappearance of SC as a result of cessation of Ig exocytosis. Secretion of Igs increased in the epithelium and glands of the digestive and respiratory tracts following massive antigenic attack in cases of acute chorioamnionitis. All of this demonstrates that SIS is a widely branching immune system which appears and acts early in the human embryo, before the lymphoid system is formed, using IgG and IgA of maternal origin. IgA and IgM-synthesized lymphocytes appear in 9-week-old fetuses.

An immunohistochemical study of the secretory immune system in human fetal membranes and decidua of the first trimester of pregnancy.

We analyzed the presence and distribution of components of the secretory immune system (SIS) in human fetal membranes (amnion, yolk sac, chorion) and decidua from the first trimester of pregnancy. Specimens from 17 embryos (4-8 weeks of pregnancy) and nine fetuses (9-12 weeks) were divided into those that had not been exposed to massive foreign antigenic effects (Group I, n = 18) and those that had suffered acute chorioamnionitis (Group II, n = 8). Positive immunostaining for secretory component (SC), joining (J) chain, IgG, IgA, and macrophages was seen from 4 to 5 weeks of development and then during the whole first trimester of pregnancy in the syncytio- and cytotrophoblasts, the amniotic epithelium, the yolk sac endoderm and decidual cells. Macrophages with J chain, IgG and IgA were found in embryonic tissues on week 4, whereas lymphocytes, including those synthesizing IgA and IgM, appeared only at the end of the first trimester of pregnancy. In the decidua, lymphocytes and macrophages were recognized during the whole period of study. In cases with chorioamnionitis (Group II), reactivity of IgG and IgA in the mentioned cells of fetuses decreased sharply while the rate of immunoreactivity of SC and J chain as well as the number of T and B lymphocytes did not change. In the decidua, the number of immune reactive cells sharply increased with the appearance of plasma cells. In the fetal membranes and decidua all the SIS components are present. We suggest that two SIS, maternal and fetal, participate in the formation of the barrier between a mother and the fetus. Both these systems have different origin and cellular content as well as different immune reactions.