The cell-adhesion molecule L1 was originally described in the nervous system.It has recently been detected in CD4+ T lymphocytes, peripheral B lymphocytes, and granulocytes in the humanimmune system and in similar leucocyte types in the murine immune system. L mediates neural recognition byCa+2, Mg+2-independent homophilic binding. In the human and murine immune systems, L1 binds to the &#8220;classical&#8221; vitronectin receptor, &#945;V&#946;3, and fibronectin receptor, &#945;5&#946;1, respectively, and abstains from homophilic binding. Homophilic L1 binding probably involves antiparallel alignment of several interactive domains. Integrin binding is mediated by a short segment of immunoglobulinlike domain 6, which includes two RGD repeats in rodent L1 and one RGD motif in human L1. L1 is modulated in activated leucocytes in vitro in parallel to L-selectin, and diverse cell types release intact L in vivo and in vitro. Released L1 can bind to laminin and adheres to the extracellular matrix of sciatic nerve, M21 melanoma, and possibly spleen and other tissues. It can support integrin-dependent cell migration and preliminary data implicate it in tumor development and transnodal lymphocyte migration.

Guni  Kadmon

Anthony M. P. Montgomery

Peter  Altevogt

L1 Makes Immunological Progress by Expanding Its Relations

The ability of human tonsillar lymphoid cells to express growth hormone receptor (hGH-N-R) was analyzed by flow cytometry. FITC-coupled recombinant human growth hormone (hGH-N) was used to reveal the receptors, in combination with phenotype markers.Unlike T cells, tonsillar B cells constitutively express the hGH-N receptor. Quiescent cells separated from activated cells by Percoll-gradient centrifugation bear fewer receptors than activated ones. Activated T cells express hGH-N-R, but the typical germinal centre CD4+CD57+ T cells do not. These latter thus appear not to be fully activated.Inside the lymph follicles, the germinal centre CD38+ B-cell population and the mantle-zone CD39+ B-cell population display similar levels of hGH-N-R expression, but receptor density is lower on dividing dark-zone CD38+CD10+ B cells.Different lymphoid-cell populations thus differ markedly in their ability to express the growth hormone receptor, in relation notably to their activation status. This highlights the link between the neuroendocrine system and the active immune defense.

Olivier Thellin

Bernard Coumans

Willy Zorzi

Ross Barnard

Georges Hennen

Ernst Heinen

Ahmed Igout

Expression of Growth Hormone Receptors by Lymphocyte subpopulations in the Human tonsil

Costimulatory signals provided by T cells are required for B cells to produce specific antibody to T-dependent antigen. We have investigated the suitability of using the CD40 culture system for the proliferation and differentiation of Ag-specific human B cells using cytomegalovirus (CMV) or tetanus toxoid (TT) as antigen. We modified the CD40 culture system (CD32- transfected L cells, anti-CD40, and IL-4) by applying a sequential cytokine stimulation and compared total B-cell cultures with antigen-specific B cells preselected by panning. The detection of specific antibody became possible when antigen-selected B cells were cultured for 7 days in the CD40 system to induce clonal expansion, followed by the addition of IL-2 and IL10 for an additional 7 days to induce plasma-cell differentiation. We conclude that our intial inability to detect specific antibody in the CD40 system is due to overgrowth of nonspecific B cell clones and that selection of antigen-specific B cells by panning overcomes this problem. Induction of antigen-specific antibody production was found to be optimal when the initial
contact with antigen during panning was limited to between 1 to 24 hours.

B. M. Schilizzi

M. C. Harmsen

T. H. The

L. De Leij

Studies on the Induction of Antigen-Specific Antibody in Anti-CD40 Cultured Human B Lymphocytes

The interactions of CD40 and CD40L have been known for some time to critically regulate B-cell responses
with respect to proliferation, isotype switching, antibody production, and memory formation.
More recent findings demonstrated that CD40 can be expressed on several other antigen-presenting cell (APC) types
such as macrophages, dendritic cells, and fibroblasts. This expression of CD40 regulates T-cell-APC interaction and
is centrally involved in a wide array of inflammatory events. Here, currently available data are reviewed
demonstrating that CD40- CD40L interactions are operational in two chronic inflammatory clinical conditions,
namely, multiple sclerosis and atherosclerosis. The functional correlates of these interactions are discussed in the
light of recent other findings, shedding light on the multiple effects of CD40- CD40L interactions.

Jon D. Laman

Mark De Boer

Bert A. 'T Hart

CD40 in Clinical Inflammation: From Multiple Sclerosis to Atherosclerosis

L. V. Rizzo

E. A. Secord

V. K. Tsiagbe

D. T. Umetsu

R. H. Dekruyff

W. J. Simmons

G. J. Thorbecke

Components Essential for the Generation of Germinal Centers

The microenvironment of secondary lymphoid organs consists of two major populations of cells, the lymphoid cells and a population of stromal cells that contribute to both tissue architecture and function. Interactions of both populations are essential for the development and control of humoral immune responses. In this study, stromal-cell preparations were obtained by a multistage process. This involved culturing 300-400-μm slices of human tonsil for 6-8 days at 25°C, trypsin digestion of the residual explant, followed by CD45-positive-cell depletion using magnetic beads, and a final period of culture for 4 days to remove remaining nonadherent cells.
Phenotypifig with a panel of monoclonal antibodies revealed that the cells express HLA-DR, CD54 (ICAM-1), CD44, but no CD45 nor a range of other markers for epithelial and endothelial cells. Immunoassays of supernatants from stromal cells revealed that IL-6 was produced constitutively, and its production was increased by treatment with TNF-α and IFN-γ. In contrast IL-1, IL-2, IL-4, IL-7, IL-8, IL-10, IL-12, TNF-α, and IFNγ were not produced. Functional tests showed that these cells express follicular dendritic cell-like properties. Coculturing of tonsilar B
cells with stromal cells resulted in enhanced proliferation and also led to increased production of immunoglobulins and IL-6, suggesting crucial signaling between these populations.

Grzegorz Skibinski

Anna Skibinska

Martine Deckers

Keith James

Tonsil Stromal-Cell Lines Expressing FDC-Like Properties: Isolation, Characterization, and Interaction with B Lymphocytes

We have recently reported that thymic B lymphocytes (TBL) are the first B-cell subpopulation
undergoing isotype switching to IgG and IgA during embryonic life. The aim of this study is to
analyze the influence of antigenic stimulation on TBL location and activity using a germ-free
(GF) newborn pig model, in which maternal antibodies and antigens do not affect B-cell
development. Immunohistological analysis showed that TBL were disseminated mainly in the
thymic medulla. There were no differences in the distribution of TBL, both in GF newborn
piglets before and after colonization with Escherichia coli and in older conventionally reared
(CONV) piglets. The number of immunoglobulin (Ig)-secreting cells measured by the ELISPOT
method was not influenced by microflora and food antigens. IgM-positive cells secreting IgM
and CD45RC-positive cells spontaneously producing IgM, IgG, and IgA were detected in
newborn thymus.Our findings suggest that TBL differentiation and Ig switching to IgG and IgA-secreting cells is
not influenced by external antigens and that the thymic microenviroment plays an important role
in this process.

B. Cukrowska

I. Trebichavský

P. Rossmann

Z. Reháková

J. ŠInkora

K. Haverson

R. Lodinová-Žádníková

H. Tlaskalová-Hogenová

Antigenic Stimuli do not Influence Thymic B Lymphocytes: A Morphological and Functional Study in
Germ-Free and Conventionally Reared Piglets

Intrathymic T-cell differentiation is under the control of the thymic microenvironment, which acts on maturing thymocytes via membrane as well as soluble products. Increasing data show that this process can be modulated by classical hormones, as exemplified herein by prolactin (PRL) and growth hormone (GH), largely secreted by the pituitary gland.Both PRL and GH stimulate the secretion of thymulin, a thymic hormone produced by thymic epithelial cells. Conversely, low levels of circulating thymulin parallel hypopituitary states. Interestingly, the enhancing effects of GH on thymulin seem to be mediated by insulinlike growth factor (IGF-1) since they can be abrogated with anti-IGF-1 or anti-IGF-l-receptor antibodies. The influence of PRL and GH on the thymic epithelium is pleiotropic: PRL enhances in vivo the expression of high-molecular-weight cytokeratins and stimulates in vitro TEC proliferation, an effect that is shared by GH and IGF-1.Differentiating T cells are also targets for the intrathymic action of PRL and GH. In vivo inoculation of a rat pituitary cell line into old rats results in restoration of the thymus, including differentiation of CD4-CD8- thymocytes into CD4+CD8+ cells. Furthermore, PRL may regulate the maintenance of thymocyte viability during the double-positive stage of thymocyte differentiation.Injections of GH into aging mice increase total thymocyte numbers and the percentage of CD3-bearing cells, as well as the Concanavalin-A mitogenic response and IL-6 production by thymocytes. Interestingly, similar findings are observed in animals treated with IGF-1. Lastly, the thymic hypoplasia observed in dwarf mice can be reversed with GH treatment.In keeping with the data summarized earlier is the detection of receptors for PRL and GH on both thymocytes and thymic epithelial cells. Importantly, recent studies indicate that both cell types can produce PRL and GH intrathymically. Similarly, production of IGF-1 and expression of a corresponding receptor has also been demonstrated.In conclusion, these data strongly indicate that the thymus is physiologically under control of pituitary hormones PRL and GH. In addition to the classical endocrine pathway, paracrine and
autocrine circuits are probably implicated in such control.

Valéria De Mello-Coelho

Wilson Savino

Marie-Catherine Postel-Vinay

Mireille Dardenne

Role of Prolactin and Growth Hormone on Thymus Physiology

The development of B cells is accompanied by their ability to specifically enter
the peripheral lymphoid tissues. Recently, we described a novel rat monoclonal antibody
(IBL-2; IgG2b/k reacting with a 26/29-kD heterodimeric structure of the cell surface.
This mAb has been found to recognize differentially the peripheral B cells of mice depending on their tissue origin.
The majority of splenic B cells as well as the mature B cells in the bone marrow were stained with this mAb,
whereas the B lymphocytes isolated from LN or Peyer's patches displayed only negligible reactivity. We extended
these observations by analyzing the relationship between the
expression of IBL-2 antigen and L-selection on the surface of B-cell precursors in the bone marrow by multiparameter flow cytometry.
Within the B220 positive compartment, a significant difference of L-selectin expression could be observed between the various IBL-2-reactive subsets. Furthermore, we investigated whether evidences
for the establishment of tissue-associated phenotypic heterogeneity similar to that found in normal mice could be found upon the adoptive transfer of normal unselected splenic lymphocytes into SCID recipients (Spl-SCID).
It has been found that a large part of the splenic B cells preserved their IBL-2 reactivity, whereas the LN B cells had lost the IBL-2 antigen in Spl-SCID. These data indicate that the phenotypic difference within the SCID mice may be the result of the migration of B lymphocytes from the spleen toward the lymph nodes, and the altered expression of the IBL-2 antigen correlates with this process.

Péter Balogh

Attila Kumánovics

Istvan Juhasz

Studies on the Tissue-Related Phenotypic Heterogeneity of Murine B Cells

Mice with inactivated TNF-LT&#945; genes have profound abnormalities of the immune system with hypoimmunoglobulinaemia, lack of lymph nodes, undifferentiated spleen, and defective Ig class switch. Transplantation of bone marrow cells from wild-type mice restored the synthesis of TNF, corrected the splenic microarchitecture, repopulated the lamina propria with IgA-producing plasma cells, and normalized the serum immunoglobulin levels of TNF-LT&#945; deficient mice. Furthermore, the formation of germinal centers in the spleen and the defective Ig class switch in response to a T-cell-dependent antigen is corrected. These data demonstrate that most TNFproducing cells are bone-marrow-derived, and that the immunodeficiency due to TNF-LT&#945; deletion can be corrected to a large extent by normal bone marrow, cell transplantation.

Bernhard  Ryffel

Michel Le Hir

Mathias  M&#252;ller

Hans-Pietro  Eugster

Correction of the TNF-LT&#945;-Deficient Phenotype by Bone Marrow Transplantation

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Journal of Immunology Research provides a platform for scientists and clinicians working in different and diverse areas of immunology and therapy.

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Chief Editor, Professor Holland, has a background focusing on researching the development of conjunctival fibrosis and the characterisation of immune responses to potential C. trachomatis vaccine candidates.

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Journal of Immunology Research

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