Julia M. Phillips-Quagliata

Differentiation pathway of Peyer's patch precursors of IgA plasma cells in the secretory immune system.

Abstract Others have shown that Peyers patch (PP) precursor cells can seed the small intestine with IgA plasma cells, whose appearance after cell transfer requires an interval of a week. The location of the precursor cells during this period is the subject of the present investigation in which the fate of radiolabeled murine PP cells was studied after intravenous transfer into primary and secondary recipients. In short-term single-transfer experiments, few radiolabeled PP blasts were found in the small intestine and only a small proportion of these contained IgA. Radiolabeled PP blasts were approximately equally distributed between mesenteric lymph nodes (MN) and peripheral lymph nodes (PN). However, a higher proportion of those which went to MN than of those which went to PN was subsequently capable of settling in the small intestine of secondary recipients and a higher proportion of those arriving in the intestine was found to contain IgA. Thus, MN were distinctly superior to PN as an intermediate site for the maturation of PP-derived IgA plasma cell precursors capable of seeding the small intestine, even when these had been injected intravenously. Treatment of PP cells with antiserum to IgA prior to their injection into primary recipients interfered with the homing of IgA precursor cells to the small intestine of secondary recipients, indicating that the precursors are already producing IgA while still in the PP. IgA-containing, radiolabeled PP cells were found in the subcapsular sinus of MN within 30 min of intravenous injection, suggesting that these cells are capable of extravasating from blood and reaching the lymph within the intestine long before they are ready to remain in the intestine as plasma cells. These results imply that the superiority of MN over PN as an intermediate site for the proliferation and differentiation of PP IgA precursor cells into IgA plasma cells capable of seeding the small intestine is due to the location of the MN in the pathway of circulation of mucosal B cells.

Prostaglandin E1 as a regulator of lymphocyte function: Selective action on B lymphocytes and synergy with procarbazine in depression of immune responses☆

The possibility that prostaglandin (PG) E1 can regulate lymphocyte function in vivo was studied. In conjunction with procarbazine hydrochloride, a powerful immunosuppressive agent whose main target is the thymus and thymus-derived (T) cells, PGE1 had a synergistic effect in prolonging homograft survival, though alone it had no effect on this immune response. The main lymphocyte target of PGE1 appeared to be bone marrow-derived (B) as determined from direct assessment of total, complement receptor and θ-positive lymphocytes in the spleen and by histological evaluation.

Origin and homing of intestinal IgA antibody-secreting cells.

The fact that IgA comprises the bodys major isotype of antibody on a biosynthetic basis is not widely appreciated because IgG, not IgA, is the predominant isotype in serum. Nevertheless, the bulk of the bodys Ig-producing cells reside in the various mucosal and exocrine sites, especially along the

The IgA/IgM Receptor Expressed on a Murine B Cell Lymphoma Is Poly-Ig Receptor

T560, a mouse B lymphoma that originated in gut-associated lymphoid tissue, expresses receptors that bind dimeric IgA and IgM in a mutually inhibitory manner but have little affinity for monomeric IgA. Evidence presented in this paper indicates that the receptor is poly-Ig receptor (pIgR) known in humans and domestic cattle to bind both IgA and IgM. The evidence includes the demonstration that binding of IgM is J chain dependent, and that pIg-precipitated receptor has an appropriate Mr of 116–120 kDa and can be detected on immunoblots with specific rabbit anti-mouse pIgR. Overlapping RT-PCR performed using template mRNA from T560 cells and oligonucleotide primer pairs designed from the published sequence of mouse liver pIgR indicate that T560 cells express mRNA virtually identical with that of the epithelial cell pIgR throughout its external, transmembrane, and intracytoplasmic coding regions. Studies using mutant IgAs suggest that the Cα2 domain of dimeric IgA is not involved in high-affinity binding to the T560 pIgR. Inasmuch as this mouse B cell pIgR binds IgM better than IgA, it is similar to human pIgR and differs from rat, mouse, and rabbit epithelial cell pIgRs that bind IgA but not IgM. Possible explanations for this difference are discussed. All clones of T560 contain some cells that spontaneously secrete both IgG2a and IgA, but all of the IgA recoverable from the medium and from cell lysates is monomeric; it cannot be converted to secretory IgA by T560 cells.

Competence of thoracic duct cells in the transfer of adjuvant disease and delayed hypersensitivity. Evidence that mycobacterial components are required for the successful transfer of the disease

Abstract Transfer of rat adjuvant disease into syngeneic recipients was achieved with lymph node and spleen cells from adjuvant injected donors, but not with washed thoracic duct (TD) cells, despite the fact that these were capable of transferring delayed hypersensitivity (DH) to PPD. Addition of mycobacteria enabled the TD cells to transfer disease. Injection of adjuvant caused accelerated development of disease in the recipients of sensitized TD cells. Since addition of mycobacterial components, probably already present in lymph node and spleen cell preparations, was necessary to transfer disease with sensitized TD cells, it appears unnecessary to invoke an autoimmune or viral etiology for the disease. It is concluded that adjuvant disease results from prolonged DH type reactions to mycobacterial components deposited in the sites of inflammation. TD cells drained late were more efficient than those drained early after cannulation in the transfer of DH to PPD. This was probably due to changes in the proportions of different cell populations present in the TD lymph.

DEVELOPMENT OF THE IgA SYSTEM IN THE MAMMARY GLAND

1) Lymphoblasts in gut-associated lymphoid tissue, committed to the production of IgA, can home to the mammary glands of syngeneic mice and differentiate there into IgA-containing plasmablasts. The phenomenon is limited to near term and lactating recipients. 2) The ability of lymphocytes originating in gut-associated lymphoid tissue and sensitized to intestinal antigens to migrate to the mammary gland can account for the specificity of milk IgA toward intestinal microorganisms and the consequent passive protection offered to suckling infants. 3) The secretory immune system of the mammary gland is apparently under hormonal control since mammotropic hormones given to virgin females can induce morphological and functional characteristics seen naturally only during pregnancy and lactation. Examples are increased numbers of IgA plasma cells and the ability to trap their circulating precursors taken from mesenteric lymph nodes.

Immunosuppression by procarbazine: I. Sites of action of the drug and effect on adjuvant arthritis and circulating antibody responses

Abstract The effect of procarbazine hydrochloride on adjuvant arthritis and on circulating antibody responses in the rat was studied. Procarbazine had a profoundly depressing effect on both adjuvant arthritis and the circulating antibody response to ovalbumin (OA). In contrast, it had no effect on the immune response to sheep erythrocytes (SRBC) alone; the presence of adjuvant, however, enhanced the response to SRBC, and this enhancement was suppressed by procarbazine. Preinjection with adjuvant enhanced the response to OA given at a different site: procarbazine treatment at the time of adjuvant injection suppressed this enhancement. These results taken in conjunction with histological observations, reinforce the idea that the initial effect of the drug is predominantly on the thymus and thymus-dependent cell populations, though prolonged treatment may also affect the bone marrow. They also give a clue to the mode of action of adjuvant in enhancing immune responsiveness. It is suggested that judicious use of procarbazine may assist fine dissection of various components of the immune response.

Cellular events in tolerance: I. Induction and loss of tolerance in neonatal and adult rats☆

Abstract Tolerance of bovine serum albumin (BSA) was induced in newborn rats by a single injection of a high dose (10 mg) of BSA. The lower doses tried either had no apparent effect or resulted in priming. Tolerance lasted for about four weeks in Wistar Furth (WF) rats and was followed by rapid recovery of responsiveness to challenge. Tolerance maintained from birth to 10.5 weeks of age by weekly injections of BSA lasted for about two weeks after the last injection; recovery then took place at about the same rate as in rats beginning to recover four weeks after a single injection at birth. Adult rats did not become tolerant even after 9 weeks of repeated injections of either high (2 and 10 mg) or low doses (1.0 and 0.1 μg) of BSA; a longer schedule with the highest dose might have achieved tolerance, since during response to challenge, recipients of the high dose made progressively less antibody than controls. Partial tolerance was induced in adult rats by injection of a very low dose of ovalbumin (OA) (55 pg/g body weight) three times per week for six weeks. The antibody made by partially tolerant rats was not of markedly different avidity from that made by controls, nor was it of a different IgG class. The effective dose was one-tenth of that which resulted in the presence of detectable antibody at the time of challenge. These findings are discussed in relation to recent hypotheses about the mechanism(s) of induction and loss of tolerance.

T-Cell help for the IgA response: The function of T cells from different lymphoid organs in regulating the proportions of plasma cells expressing various isotypes☆

Differential distribution of IgA-specific primed Lyt 2- T cells (TH) in favor of gut-associated lymphoid tissue (GALT) has been proposed to account for the high proportion of IgA-producing plasma cells at mucosal versus nonmucosal sites. We find, however, that GALT TH primed enterically with sheep red blood cells (SRBC) contain no more help for IgA responses than peripheral lymph node (PN) TH primed subcutaneously. Moreover, GALT TH are only poorly primed by enterically administered soluble protein antigen and therefore provide less help for all isotypes than PN TH primed subcutaneously with the same antigen. On the other hand, supernatants of GALT TH stimulated with concanavalin A (Con A) in vitro do help higher IgA:IgG plaque-forming cell (PFC) ratios in cultures with 2,4, 6-trinitrophenyl-SRBC (TNP-SRBC) than supernatants from PN and spleen, indicating that, when appropriately stimulated, GALT TH are capable of promoting relatively higher IgA responses than TH from other sources. Responses elicited by either SRBC-primed TH or splenic Con A supernatants in the presence of TNP-SRBC contained higher IgA:IgG PFC ratios than those elicited by linked recognition in the presence of haptenated soluble protein carrier.

Cellular events in tolerance. II. Thymus-bone marrow cell cooperation in the immune response to BSA in Wistar Furth rats.

Abstract Normal bone marrow cells from Wistar Furth rats were competent to transfer immune responsiveness to bovine serum albumin to thymectomised, irradiated, syngeneic recipients. When the bone marrow cells were taken from donors thymectomised early in life they were incompetent, but competence was restored by addition of normal thymus cells. It was concluded that normal Wistar Furth bone marrow cells contain some thymus-derived cells. Thymus cells from tolerant donors were less effective in cooperation with bone marrow cells, however the thymus cells appeared less tolerant than their donors.