IgG-producing Plasma Cells Research Articles

IL-2 Producing Memory CD4+ T Lymphocytes Are Closely Associated with the Generation of IgG-Secreting Plasma Cells

The role of specific CD4(+) T cell subsets in the induction of humoral immune responses in humans is largely unknown. In this study, the generation of hepatitis B surface Ag-specific CD4(+) T lymphocytes following vaccination was closely monitored and characterized at the single-cell level. The appearance and absolute numbers of hepatitis B surface Ag-specific IL-2 producing effector memory CD4(+) T lymphocytes was solely and tightly related to Ab titers reached. This relation remained present many years after vaccination. Subsequently, a relation was found between Ab titers and number of IL-2 producing memory CD4(+) T lymphocytes for various other Ags. These observations matched the findings of an in vitro assay, using different T cell subsets to induce B cell differentiation into IgG-producing plasma cells. By depleting for IL-2 producing memory T cells, we demonstrated that these cells are important for B cell differentiation into IgG-producing plasma cells. Finally, blocking the action of IL-2 with an IL-2R-alpha Ab inhibited the differentiation of B lymphocytes into IgG-producing plasma cells. Based on these findings, we conclude that the development of Ag-specific IL-2-producing memory T cells appears to be essential for the development of IgG-secreting plasma cells in humans.

Detection of Epstein–Barr virus-encoded small RNA-expressed myofibroblasts and IgG4-producing plasma cells in sclerosing angiomatoid nodular transformation of the spleen

Sclerosing angiomatoid nodular transformation (SANT) of the spleen is a rare inflammatory tumor-like lesion composed of vascular nodules and non-neoplastic stroma including spindle cells and inflammatory cells. The focus of our study was on the stromal proliferating process in SANT. Nine cases of SANT were examined. All cases showed alpha-smooth muscle actin (alpha-SMA) and vimentin on the spindle cells but not CD21, CD31, CD34, CD68, desmin, S100, human herpes virus-8, or anaplastic lymphoma kinase-1. In one case, 20-30% of the myofibroblasts in Epstein-Barr-virus (EBV)-positive spindle cells were detected using double-labeling immunohistochemistry for alpha-SMA and EBV-encoded small RNA in situ hybridization. A quantitative analysis of IgG and IgG4-positive plasma cells (pPCs) in SANT was performed. The median densities of IgG-pPCs and IgG4-pPCs in SANT were approximately four-fold and 13-fold higher than those in the normal spleens, respectively. In addition, there was a statistically significant increase of IgG4/IgG-pPCs ratio in SANT in comparison to the control specimens. In conclusion, the fibrogenesis in a subset of SANT may be associated with EBV-infected myofibroblasts in an overlapping immune reaction indicated by the presence of infiltrating IgG4-pPCs. Further investigation is needed to elucidate the association between SANT and IgG4-related sclerosing disease.

APRIL secreted by neutrophils binds to heparan sulfate proteoglycans to create plasma cell niches in human mucosa

The bone marrow constitutes a favorable environment for long-lived antibody-secreting plasma cells, providing blood-circulating antibody. Plasma cells are also present in mucosa-associated lymphoid tissue (MALT) to mediate local frontline immunity, but how plasma cell survival there is regulated is not known. Here we report that a proliferation-inducing ligand (APRIL) promoted survival of human upper and lower MALT plasma cells by upregulating expression of the antiapoptotic proteins bcl-2, bcl-xL, and mcl-1. The in situ localization of APRIL was consistent with such a prosurvival role in MALT. In upper MALT, tonsillar epithelium produced APRIL. Upon infection, APRIL production increased considerably when APRIL-secreting neutrophils recruited from the blood infiltrated the crypt epithelium. Heparan sulfate proteoglycans (HSPGs) retained secreted APRIL in the subepithelium of the infected zone to create APRIL-rich niches, wherein IgG-producing plasma cells accumulated. In lower MALT, neutrophils were the unique source of APRIL, giving rise to similar niches for IgA-producing plasmocytes in villi of lamina propria. Furthermore, we found that mucosal humoral immunity in APRIL-deficient mice is less persistent than in WT mice. Hence, production of APRIL by inflammation-recruited neutrophils may create plasma cell niches in MALT to sustain a local antibody production.

Recognizing Immunoglobulin G4-Related Overlap Syndromes in Patients with Pancreatic and Hepatobiliary Diseases

The first description of autoimmune pancreatitis and elevated serum immunoglobulin-G4 (IgG4) in 2001 heralded further reports of several related autoimmune diseases with raised IgG4 levels. It is now recognized that a spectrum of overlap syndromes associated with increased IgG4 and biopsy evidence of IgG4-producing plasma cells, which has now been convincingly linked with cholangitis, autoimmune hepatitis, Sjögren's syndrome, nephritis and retroperitoneal fibrosis. Collectively, this disease cluster is referred to as IgG4-related systemic disease. The importance of making the correct diagnosis is underscored by the management of individuals with IgG4-related systemic disease. In the first instance, patients generally have a dramatic response to immunosuppressive therapy, whereas patients with other forms of cholangitis and pancreatitis do not. Also, surgical management of pancreatic malignancy can be avoided once the correct diagnosis of IgG4-related disease has been made. In the present review, an overview of the current information regarding the role of IgG4 and IgG4-positive cells affecting the biliary system, pancreas and liver is provided.

Severe Necrotizing Encephalitis in a Yorkshire Terrier: Topographic and Immunohistochemical Study

Necrotizing encephalitis of the Yorkshire terrier is a chronic non-suppurative encephalitis that was reported in approximately 15 cases worldwide. We report the case of a 10-year-old female Yorkshire terrier with gross evidence of severe cortical degeneration and necrosis. Microscopically, affected areas were mainly located in the cortical white matter and in the mesencephalon without implication of the cerebellum. Cavitation necrosis, demyelination, gemistocytic astrocytosis, marked perivascular lymphocytic cuffing with a diffuse lymphocytic/histiocytic/gitter cell infiltration characterized the lesions. Immunohistochemical analysis identified the major infiltration of T lymphocytes and macrophages with implication of some cytotoxic lymphocytes and IgG-producing plasma cells; depositions of IgG in the affected white matter were also observed. Specific stains did not reveal fungal, protozoal or bacterial organisms and reverse transcriptase-polymerase chain reaction analysis for distemper virus was also negative. The lympho-histiocytic inflammation suggests a T-cell-mediated and a delayed-type immune reaction as a possible pathogenic mechanism for this brain disorder.

Comparable Long-Term Persistence of Anti-FVIII Antibodies in Hemophilic E17 Mice on Different Genetic Backgrounds Despite Significant Differences in the Amplitude of the Immune Responses.

About 30% of patients with severe hemophilia A develop neutralizing antibodies against FVIII (FVIII inhibitors) following replacement therapy. The type of FVIII gene mutation as well as other predisposing genetic factors contribute to the inhibitor phenotype. Based on these findings, we asked if the genetic background modulates the long-term persistence of anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells in the E17 murine hemophilia model. Furthermore, we asked if the recently described inhibition of memory-B-cell re-stimulation by high doses of FVIII is influenced by the genetic background of the murine model.E17 mice on two different genetic backgrounds (C57Bl/6J and Balb/c) were treated with four doses of 200 ng human FVIII at weekly intervals. Anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells were followed up to 12 months after the last dose of FVIII. Antibody titers and subclasses of antibodies (IgM, IgG1, IgG2a, IgG2b, IgG3) were measured by ELISA. Antibody secreting plasma cells in spleen and bone marrow were detected by ELISPOT as described (Hausl et al., Thromb Haemost 2002). The re-stimulation of FVIII-specific memory B cells was studied as described recently (Hausl et al., Blood 2005). Anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells were first detectable in E17 Balb/c mice. IgM antibodies in the circulation and IgM secreting plasma cells in the spleen were observed after the first dose of FVIII, IgG antibodies and IgG secreting plasma cells after the second dose. No anti-FVIII antibodies after the first dose of FVIII were observed in E17 C57BL/6J mice but both IgM and IgG antibodies as well as IgM and IgG producing plasma cells were detectable after the second dose of FVIII. The antibody response involved all IgG subclasses in both mouse strains. However, IgG1 was dominant in E17 Balb/c mice whereas IgG2a was dominant in E17 C57BL/6J mice.When the in vitro restimulation of FVIII-specific memory B cells was examined, similar patterns were observed for both mouse strains. Low concentrations of FVIII between 10 and 100 ng/ml FVIII restimulated memory B cells and induced their differentiation into antibody secreting plasma cells whereas high concentrations of FVIII between 1,000 and 20,000 ng/ml FVIII inhibited memory-B-cell-restimulation. These results indicate that the dose-dependent effect of FVIII on the restimulation of FVIII-specific memory B cells does not depend on the genetic background.The major difference between both hemophilic mouse strains was the amplitude of the anti-FVIII immune response. Peak titers of anti-FVIII antibodies and peak concentrations of anti-FVIII antibody secreting plasma cells in spleen and bone marrow were significantly higher in E17 C57BL/6J mice than in E17 Balb/c mice. Whether or not higher ELISA titers correlate with higher Bethesda titers of neutralizing antibodies is currently being investigated. Despite the substantial differences in the amplitude of the immune response, anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells persisted for the whole observation period of 12 months after the last dose of FVIII in both mouse strains.We conclude that the amplitude of the anti-FVIII immune response in hemophilic mice is significantly different between E17 C57BL/6J and E17 Balb/c mice. However, the persistence of the immune response is comparable.

Heterogeneity of IgG Glycosylation in Adult Periodontal Disease

Periodontal disease is a chronic inflammatory disease of bacterial etiology. In many other chronic inflammatory diseases, IgG glycans are galactose-deficient and thus capable of complement activation through the lectin pathway. In this study, we examined whether IgG in serum and gingival crevicular fluid, and IgG locally produced by plasma cells in gingiva of periodontal disease patients, display altered glycosylation. We developed a lectin-ELISA to measure levels of galactose-deficient IgG in the fluids and immunofluorescence staining to detect galactose-deficient IgG-producing cells in gingiva. Our results indicated higher levels of galactose-deficient IgG in sera and gingival crevicular fluid from periodontal disease patients, compared with levels in healthy controls. Furthermore, gingivae from periodontal disease patients exhibited infiltration of IgG-producing plasma cells; many of them contained galactose-deficient IgG in the cytoplasm. Analysis of our data suggests that IgG secreted by B-cells was aberrantly glycosylated, which resulted in the production of pro-inflammatory galactose-deficient IgG.

Clinical involvement of the tonsillar immune system in IgA nephropathy

The temporal association of tonsillitis and hematuria or proteinuria in IgA nephropathy suggests that there might be a link between the physiological properties of the secondary lymphoid organ that tonsils represent and the mesangial deposition of IgA characteristic of this nephropathy. A number of clinical and ex-vivo data support this hypothesis. One of the earliest was the demonstration of the dimeric nature of mesangial IgA, composed of IgA monomers linked by a J chain, yet lacking the polyIg receptor acquired by secretory IgA during transcytosis through epithelial cells. This molecular structure is that of IgA synthesized in human tonsils, the epithelium of which lacks polyIg receptor. Moreover, tonsils from patients with IgA nephropathy display an abnormal partition of IgG and IgA producing plasma cells associated with a significantly developed web of high endothelial venules. IgA nephropathy could thus be in part related to an alteration of IgA precursors homing in tonsils. Tonsillectomy thus would present the advantage of removing an abnormally functioning source of dimeric IgA. Performed early enough in the course of the renal disease, tonsillectomy could suffice to halt the development of the nephropathy and restore the kidneys to health.

Rare Concomitance of Primary Systemic Amyloidosis with Immunoglobulin M Monoclonal Gammopathy or Waldenstrom Macroglobulinemia.

Introduction: Primary systemic amyloidosis occurs when a clonal plasma cell population secretes light chains (or light chain fragments) that deposit in tissues as amyloid and cause organ failure and ultimately patient death. Primary systemic amyloidosis generally results from non-proliferative small populations of plasma cells. While it is known that IgG, IgA and light chain producing plasma cells can secrete amyloid in association with myeloma, fewer medical professionals recognize that IgM-secreting lymphoplasmacytic cells can produce amyloid proteins. When monoclonal IgM secreting marrow lymphocytes are present, amyloidosis can result with or without overt Waldenstrom Macroglobulinemia.Patients and Methods: All patients seen at the Mayo Clinic between January 1968 and August 2000 with both a serum IgM monoclonal protein and biopsy-proven amyloidosis were analyzed. The Mayo Clinic Dysproteinemia Database recognized 128 patients (42 female, 86 male) with a median age of 65 years.Results: Seventy-two percent (n=92) of the patients have died with a median survival of 1.72 years following biopsy proven amyloidosis (figure 1). Median serum IgM monoclonal spike was 1.38 g/dL. In addition, serum IgM kappa to lambda light chain ratios (1:3) were found to be reversed in patients with IgM gammopathy when amyloid was present (compared to the reverse ratio (3:1) in patients with Waldenstrom macroglobulinemia in the absence of amyloidosis). Subcutaneous fat, rectum and bone marrow revealed amyloid in 72%, 69% and 70%, respectively, providing non-invasive techniques for amyloidosis diagnosis without the risks of bleeding associated with renal or hepatic percutaneous biopsy. Variables not shown to affect survival included the following: age, gender, serum M spike, urine protein, alkaline phosphatase, creatinine, light chain isotype, ejection fraction, and percent marrow plasma cells. The presence of amyloid cardiomyopathy (defined as a cardiac interventricular septal thickness greater than 12 mm.) was the only variable to adversely affect survival. Of the patients with echocardiographic evidence of cardiomyopathy, the median survival was 10.8 months. In contrast, the patients without echocardiographic evidence of cardiomyopathy at diagnosis had a median survival of 39 months (figure 2).Conclusion: Amyloidosis is underappreciated and should be considered in the differential diagnosis of all patients presenting with IgM gammopathy. Patients found to have amyloidosis in this setting should be tested for amyloid cardiomyopathy, as its presence predicts poor outcome. Lambda light chain in serum IgM samples should increase the index of suspicion for the presence of amyloid since IgM lambda is present in only 25% of IgM MGUS or Macroglobulinemia patients but is seen in 75% of IgM amyloidosis patients. [Display omitted]

Pathological and immunohistochemical study of the abomasum and abomasal lymph nodes in goats experimentally infected with Haemonchus contortus.

Histopathological changes and the distributions of T and B lymphocytes and IgG producing plasma cells were recorded in the abomasum and abomasal lymph nodes of goats 3, 7 and 21 weeks post-infection (wpi) after an experimental infection with H. contortus. The low rate of worm recovery by 3 wpi (5.6%) might have been due to larvae death as suggested by the presence of granulomas in the abomasal mucosa at 3 and 7 wpi, or simply due to a poor larval establishment. Marked increase in the secretion of mucus by mucous cells together with an abundant infiltration of eosinophils, mast cells, CD3+ T lymphocytes, CD79a+ B cells, IgG+ plasma cells and globule leukocytes were recorded in the abomasal mucosa, especially at 7 wpi. Except for the globule leukocytes, this reaction decreased substantially by week 21, suggesting this cell type may have been involved in rejection of adult nematodes. The abomasal lymph nodes showed marked hyperplasia, particularly of CD79a+ B cells and IgG+ plasma cells in all infected goats. These reactions may have been responsible for the reduction in the number of worms found in the abomasum between 3 and 7 wpi.

Effects of T-lymphocyte-dependent and -independent immunity on cholinergic enzyme activity in mouse lacrimal gland.

The nature of the immune response following ocular immunization with a protein and a polysaccharide and the effects such immunization have on the activities of cholinergic enzymes in the lacrimal glands of BALB/c mice were examined. Lacrimal glands are highly innervated by sympathetic and parasympathetic nerve fibres and are involved in mucosal immunity and therefore are excellent sites to study neuro-immune interactions. In this report, a T-lymphocyte-dependent protein antigen, keyhole limpet haemocyanin (KLH) and a T-lymphocyte-independent polysaccharide antigen, dextran (DEX) were administered topically to the eyes or intraperitoneally injected. Both routes of immunization produced a strong serum antibody response when KLH was the antigen. DEX, however, evoked a serum antibody response only after intraperitoneal administration. Eosin-haematoxylin staining indicated no histological abnormality or inflammatory changes in any immunized lacrimal glands, but immuno-staining revealed that only in the KLH-treated tissues were IgG-producing plasma cells discernible. Furthermore, KLH-specific antibody was also detectable using an immuno-blot assay in lacrimal glands. Polymerase chain reaction analysis with cytokine-specific primers revealed induction of interleukin-4 (lL-4) in KLH-treated lacrimal glands, but not in DEX or unimmunized tissues. Thus, the nature of the antigen seems important in the induction of the immune response in lacrimal glands. To delineate the effects that immunogenic differences might have on the activities of the cholinergic enzymes, choline acetyl-transferase (ChAT) and acetylcholinesterase (AChE) were assayed using radiolabelled substrates and measuring labelled products. Both ChAT and AChE activities were influenced following KLH immunization, while DEX had only transient effects on ChAT. This is possibly due to the fact that KLH, a protein antigen, is the effective inducer of the specific immune response in the lacrimal gland, while DEX is not. Experimental Physiology (2001) 86.2, 169-176.

IgG antibodies against human papillomavirus type 16 E7 proteins in cervicovaginal washing fluid from patients with cervical neoplasia.

Little information is available about the cervicovaginal mucosal antibodies against human papillomavirus (HPV) proteins. In this study specific IgG antibodies against HPV 16 E7 protein were determined in paired samples of cervicovaginal washing fluid and serum from patients with cervical cancer (n = 22), cervical intraepithelial neoplasia (CIN) (n = 38), healthy individuals (n = 22), and serum from children (n = 41) by a radioactive immunoprecipitation assay (RIPA). HPV 16 E7 specific IgG antibodies were found in cervicovaginal washings (n = 8) and in sera (n = 8) of the patients with cervical cancer. About 60% of the patients with HPV 16 positive cervical cancer had HPV 16 E7 specific IgG antibodies. Titration studies showed that the IgG antibody reactivity in cervicovaginal washings was higher than in the paired serum samples of six patients with cervical cancer (P < 0.001). In the CIN group we found no IgG reactivity in the serum, but in five patients we found a low IgG reactivity in the cervicovaginal washings. No IgG reactivity was found in cervicovaginal washings and sera from healthy individuals and sera from children. HPV 16 E7 specific IgG antibodies seem to be locally produced in a number of patients with HPV 16 positive (pre)malignant cervical lesions. For more definitive evidence for the local production of these antibodies immunostaining should be performed to demonstrate the presence of specific anti-HPV 16 E7 IgG producing plasma cells in the cervical epithelium.

Relative distribution of plasma cells expressing immunoglobulin G subclass mRNA in human dental periapical lesions using in situ hybridization

Immunoglobulin G (IgG)-producing plasma cells are the predominant immunoglobulin secreting plasma cells in human dental periapical lesions, compared with immunoglobulin A- and immunoglobulin M-producing plasma cells. In this study, the cells expressing mRNA, that encoded the distinct IgG subclasses, were detected using an in situ hybridization technique in 25 periapical lesions. These lesions consisted of 14 periapical granulomas and 11 radicular cysts. Four oligonucleotide probes were chemically synthesized from IgG subclass-specific hinge region genes to ensure specificity of the probes. Plasma cells expressing mRNA, which coded for the IgG subclasses, were detected in formalin-fixed/paraffin wax-embedded sections. Background staining was negligible in all of the sections tested. The in situ hybridization method used in this study was both specific and sensitive for the detection of mRNA encoding each of the four distinct IgG subclasses, whereas the cells retained good morphology. The relative proportions of plasma cells expressing each of the IgG subclass-specific mRNAs in both granulomas and cysts were as follows: IgG1 (57.4 and 55.5%); IgG2 (34.1 and 34.6%); IgG3 (4.0 and 4.3%); and IgG4 (4.0 and 5.5%). There were no significant differences between the percentages of plasma cells expressing each of the IgG subclass mRNAs between the two types of lesions. IgG1 producing plasma cells comprised the highest proportion of IgG-producing plasma cells in both types of periapical lesion. IgG2-producing plasma cells were next in abundance, followed by plasma cells for either IgG3 or IgG4, which were in roughly equivalent numbers.

The gingival plasma cell infiltrate in renal transplant patients on an immunosuppressive regime

Treatment with immunosuppressive agents inhibits gingival inflammation and progression of periodontitis in humans. We examined the numbers and the isotype distribution of immunoglobulin-producing plasma cells by immunohistochemistry in gingival specimens taken from renal transplant recipients receiving immunosuppressive agents (IS), and from otherwise comparable systemically healthy patients. The immunosuppressed patient group had significantly (P < 0.05) fewer IgG-, IgA-, IgG1-, IgG2-, and IgG4-producing plasma cells in the connective tissue adjacent to the pocket epithelium. The reduced numbers of such patients with quiescent periodontal disease support the contention that high counts of plasma cells are indicative of more severe disease.

The lymphoid substance of the chicken's harderian gland is organized in two histologically distinct compartments.

Light and electron microscopical investigations revealed that the lymphoid structure of the chicken Harderian gland is organized in different histological frameworks. In the head the surface epithelium of the central canal can be classified as a lymphoepithelial tissue which covers the dense lymphoid substance. It consists of small and medium-sized lymphocytes, dendritic-like cells, and occasional macrophages. High endothelial venules are associated with intense lymphocyte migration and homing that gives circumstantial evidence for a T-dependent region, as found in a secondary lymphoid organ. The B-dependent germinal centers are also common structural units of the head region's lymphoid substance. The body of the gland is loaded with plasma cells of different maturation stages. They immigrate into the epithelium of the central canal and produce IgM and IgA. Only a few scattered IgG producing plasma cells can be found in the gland of Harder. This plasmocytic region accounts for the immunosurveillance on the conjunctiva and in the upper respiratory tract through antibody production against bacterial or parasitic infections. In both the head and body regions of the gland, anti-B-L (anti-Ia) antibody recognized scattered elongated cells which might represent dendritic cells. The immunological relationship between the two histologically different parts of the Harderian gland is unknown, but we speculate that the dense lymphoid tissue with high endothelial venule receives the blood-borne, immunologically mature, but uncommitted B cells. By the influence of local antigen stimulus, these B cells transform to plasma cells which gradually appear in the body of the gland. The lymphoid structures of the head and the body fulfill the function of secondary and tertiary lymphoid organs, respectively.

The lymphoid substance of the chicken's Harderian gland is organized in two histologically distinct compartments

Light and electron microscopical investigations revealed that the lymphoid structure of the chicken Harderian gland is organized in different histological frameworks. In the head the surface epithelium of the central canal can be classified as a lymphoepithelial tissue which covers the dense lymphoid substance. It consists of small and medium-sized lymphocytes, dendritic-like cells, and occasional macrophages. High endothelial venules are associated with intense lymphocyte migration and homing that gives circumstantial evidence for a T-dependent region, as found in a secondary lymphoid organ. The B-dependent germinal centers are also common structural units of the head region's lymphoid substance. The body of the gland is loaded with plasma cells of different maturation stages. They immigrate into the epithelium of the central canal and produce IgM and IgA. Only a few scattered IgG producing plasma cells can be found in the gland of Harder. This plasmocytic region accounts for the immunosurveillance on the conjunctiva and in the upper respiratory tract through antibody production against bacterial or parasitic infections. In both the head and body regions of the gland, anti-B-L (anti-Ia) antibody recognized scattered elongated cells which might represent dendritic cells. The immunological relationship between the two histologically different parts of the Harderian gland is unknown, but we speculate that the dense lymphoid tissue with high endothelial venule receives the blood-borne, immunologically mature, but uncommitted B cells. By the influence of local antigen stimulus, these B cells transform to plasma cells which gradually appear in the body of the gland. The lymphoid structures of the head and the body fulfill the function of secondary and tertiary lymphoid organs, respectively. © 1996 Wiley-Liss, Inc.

Blood Transfusion-Induced Immunomodulation

Blood Transfusion-Induced Immunomodulation

Characterization of Idiotype-Specific I-E d-Restricted T Suppressor Lymphocytes which Confine Immunoglobulin Class Expression to IgM in the Anti-α (1- > 3) Dextran B 1355 S Response of BALB/c Mice

The humoral immune response of conventionally raised BALB/c mice to the so-called «thymus independent» antigen α (1- > 3) Dextran B 1355 S (Dex) is predominantly of the IgM class. The response is further characterized by Igh a allotype linkage and the dominance of the public idiotypes (Id) J558 and MOPC 104. In germfree raised BALB/c and in BALB/c nu/nu mice immunized with the same antigen an additional IgG response of the public Id is observed. Analysis of the regulation of the class expression reveals existence of specific Ts cells in euthymic mice which must have been activated pre- or perinatally by exposure to environmental bacterial antigens. They permit or enforce differentiation of Dex-specific B cells into Bγ memory cells without allowing further development into IgG producing plasma cells. An analogue of these splenic Ts cells has now been cloned and identified as an I-E d restricted Id-specific T cell with exactly the properties ascribed above to the splenic Ts cells. This paper describes phenotypical and functional properties of the Ts cell clone 178-4. It evaluates this clone's role in controlling efficient anti-bacterial IgM-mediated immunity under conditions where a class switch to IgG antibody production is actively suppressed; possibly as a measure to avoid hazardous autoimmune reactions on the basis of crossreaction and antigenic mimicry between polysaccharide antigens.

Development of autoimmune disease in SCID mice populated with long-term "in vitro" proliferating (NZB x NZW)F1 pre-B cells.

Pre-B cell lines proliferating for several months on stromal cells in the presence of interleukin 7 (IL-7) were established from fetal liver of (NZB x NZW)F1 mice. They express the B lineage-specific markers PB76, B220, and VpreB, but do not express surface immunoglobulin (sIg). Upon removal of IL-7 from the culture, they differentiate to sIg+ B cells that can then be stimulated by lipopolysaccharide to become IgM-secreting cells. Transfer of these pre-B cell lines into SCID mice leads to hypergammaglobulinemia of IgM (600-900 micrograms/ml), IgG2a (1-3 mg/ml), and IgG3 (300-500 micrograms/ml) for the next 3-5 mo. The spleen appears populated with (NZB x NZW)F1-derived pre-B cells, few B cells, and many IgM and/or IgG-producing plasma cells. In contrast, SCID mice populated with pre-B cell lines of normal (C57BL/6 x DBA/2)F1 mouse fetal liver develop normal levels of serum IgM (approximately 100-300 micrograms/ml), almost no detectable levels of IgG, and no plasma cell hyperplasia. The (NZB x NZW)F1 pre-B cell-populated SCID mice contain elevated serum titers of IgG antinuclear autoantibodies, but no retroviral gp70-specific nor erythrocyte-specific autoantibodies. Up to 20% of the SCID mice develop proteinuria as a consequence of IgG deposits in the kidney glomeruli during a 7-mo period of observation. All signs of autoimmune disease seen in these mice are independent of the sex of the SCID host. This experimental system provides a distinction between the disease-determining (NZB x NZW)F1 genes, which are expressed in the B lymphocyte lineage and cause the development of the disease, from those expressed in other cell lineages which only modulate its progression.

Production and distribution of immunoglobulin-bearing cells in the intestine of young pigs infected with Ascaris suum

Pigs of 10 days-1 month old were orally infected with eggs of Ascaris suum at different rates and inoculation schedules. Histological sections from various parts of the small intestines were prepared to observe the production and localization of immunoglobulin-bearing cells. Fluorescent antibody and immunoperoxidase staining methods were used to determine the number of IgM-, IgA- and IgG-producing plasma cells in the intestinal lamina propria. Significant increases in immunoglobulin-bearing cells were observed in those pigs which received single inoculations of A. suum eggs. Pigs infected every 2,4,8 and 10 days with 10,000-20,000 embryonated eggs showed numerical increases in IgM-bearing cells. Increases in IgA-bearing cells were noted in pigs which received the higher number of eggs every 8-10 days. Higher concentrations of IgA- and IgM-bearing cells were observed in the jejunal mucosa of infected pigs as compared to those in the duodenum and ileum.