Cryptopatches and isolated lymphoid follicles: dynamic lymphoid tissues dispensable for the generation of intraepithelial lymphocytes

Abstract We describe the identification, experimental transmission, and pathogenesis of a naturally occurring powerfully immunosuppressive isolate of feline leukemia virus (designated here as FeLV-FAIDS) which induces fatal acquired immunodeficiency syndrome (AIDS) in 100% (25 of 25) of persistently viremic experimentally infected specific pathogen- free (SPF) cats after predictable survival periods ranging from less than 3 months (acute immunodeficiency syndrome) to greater than one year (chronic immunodeficiency syndrome), depending on the age of the cat at time of virus exposure. The pathogenesis of FeLV-FAIDS-induced feline immunodeficiency disease is characterized by: a prodromal period of largely asymptomatic viremia; progressive weight loss, lymphoid hyperplasia associated with viral replication in lymphoid follicles, lymphoid depletion associated with extinction of viral replication in lymphoid follicles, intractable diarrhea associated with necrosis of intestinal crypt epithelium, lymphopenia, suppressed lymphocyte blastogenesis, impaired cutaneous allograft rejection, hypogammaglobulinemia, and opportunistic infections such as bacterial respiratory disease and necrotizing stomatitis. The clinical onset of immunodeficiency syndrome correlates with the replication of a specific FeLV-FAIDS viral variant, detected principally as unintegrated viral DNA, in bone marrow, lymphoid tissues, and intestine. Two of seven cats with chronic immunodeficiency disease that survived greater than 1 year after inoculation developed lymphoma affecting the marrow, intestine, spleen, and mesenteric nodes. Experimentally induced feline immunodeficiency syndrome, therefore, is a rapid and consistent in vivo model for prospective studies of the viral genetic determinants, pathogenesis, prevention, and therapy of retrovirus-induced immunodeficiency disease.

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THE LYMPHOID TISSUES AND IMMUNE RESPONSES OF NEONATALLY THYMECTOMIZED MICE BEARING THYMUS TISSUE IN MILLIPORE DIFFUSION CHAMBERS

Journal of Experimental Medicine ◽

10.1084/jem.119.1.177 ◽

1964 ◽

Vol 119 (1) ◽

pp. 177-194 ◽

Cited By ~ 133

Author(s):

David Osoba ◽

J. F. A. P. Miller

Keyword(s):

Immune Responses ◽

Intestinal Tract ◽

Lymphoid Cells ◽

Lymphoid Tissues ◽

Lymphoid Follicles ◽

Diffusion Chambers ◽

Wasting Syndrome ◽

Thymus Tissue ◽

Reticular Cells ◽

Thymectomized Mice

Neonatally thymectomized mice were implanted intraperitoneally at 7 days of age with Millipore diffusion chambers containing either embryonic or neonatal thymus tissue. Mice which received either empty diffusion chambers or no further treatment following neonatal thymectomy served as controls. In contrast to these controls, most of the mice implanted with thymus-filled chambers gained weight satisfactorily, did not develop a wasting syndrome, and had the capacity to produce serum antibodies in response to sheep erythrocytes and to reject allogeneic skin grafts. Lymphoid follicles were present in the lymph nodes, spleen, and intestinal tract of the implanted mice but most still showed some diminution in the population of lymphocytes in both blood and tissues. Control thymectomized mice had markedly depleted lymphoid tissues and low peripheral blood lymphocyte levels. The tissue recovered after 1 to 2 months from the diffusion chambers showed only epithelial-reticular cells but no lymphoid cells. It is suggested that a humoral factor produced by the thymus epithelial-reticular complex may be responsible for endowing lymphoid cells with immunological competence.

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Binding of Intimin from Enteropathogenic Escherichia coli to Lymphocytes and Its Functional Consequences

Infection and Immunity ◽

10.1128/iai.71.5.2960-2965.2003 ◽

2003 ◽

Vol 71 (5) ◽

pp. 2960-2965 ◽

Cited By ~ 6

Author(s):

Nathalie S. Gonçalves ◽

Christine Hale ◽

Gordon Dougan ◽

Gad Frankel ◽

Thomas T. MacDonald

Keyword(s):

Escherichia Coli ◽

T Cells ◽

Lamina Propria ◽

Cd4 T Cells ◽

Intraepithelial Lymphocytes ◽

Lymphoid Tissues ◽

Enteropathogenic Escherichia Coli ◽

Mesenteric Lymph ◽

Fluorescent Beads ◽

Functional Consequences

ABSTRACT Intimin-conjugated fluorescent beads bind to spleen CD4 T cells and Peyer's patch, mesenteric lymph node, and cecal follicle lymphocytes, with less binding to lamina propria T cells and intraepithelial lymphocytes. Intimin costimulates proliferation of spleen CD4 T cells and cells from organized lymphoid tissues but does not costimulate cells from the lamina propria of normal or inflamed colon.

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Distribution of complement receptor subtypes in non-Hodgkin's lymphomas of B-cell origin

Blood ◽

10.1182/blood.v58.1.20.20 ◽

1981 ◽

Vol 58 (1) ◽

pp. 20-26 ◽

Cited By ~ 16

Author(s):

J Cossman ◽

ES Jaffe

Keyword(s):

B Cell ◽

Lymphocytic Leukemia ◽

Lymphoid Tissues ◽

Receptor Subtypes ◽

Complement Receptor ◽

B Cell Differentiation ◽

Lymphoid Follicles ◽

Surface Receptors ◽

Cr2 Cells ◽

Hodgkin's Lymphomas

Abstract Surface receptors specific for either the C4b (CR1) or C3d (CR2) component of complement were examined on the neoplastic cells from 30 cases of non-Hodgkin's lymphoma of B-cell origin and on cells derived from 9 normal lymphoid tissues. Lymphocyte suspensions from non- neoplastic peripheral blood, tonsils, and lymph node contained three categories of complement receptor lymphocytes (CRL): cells with receptors for both C4b and C3d (CR1+, CR2+); cells with receptors for C4b but not C3d (CR1+, CR2-), and cells with receptors for C3d but not C4b (CR1-, CR2+). The mean of the proportion of total CRL expressing receptors only of C3d (CR1-, CR2+) was 0.35 for non-neoplastic tissues and 0.28 for malignant lymphomas of follicular center cell (FCC) origin. However, the proportion of cells with this phenotype was significantly higher in well differentiated lymphocytic lymphomas (WDL) and chronic lymphocytic leukemia (CLL) (0.65) and in intermediately differentiated lymphocytic lymphomas (IDL) (0.59). Histologic compartmentalization of the CRL subtypes was observed in frozen sections of normal lymphoid tissue. CR1+ cells were present in lymphoid follicles interfollicular areas, and in splenic red pulp. CR2+ cells were confined to lymphoid follicles. These findings strongly suggest that complement receptor phenotypes may be useful markers of B-cell differentiation.

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Conjunctiva-associated Lymphoid Tissue (CALT) in Normal and Bordetella avium-infected Turkeys

Veterinary Pathology ◽

10.1177/030098588902600306 ◽

1989 ◽

Vol 26 (3) ◽

pp. 222-230 ◽

Cited By ~ 30

Author(s):

A. S. Fix ◽

L. H. Arp

Keyword(s):

Electron Microscopy ◽

Endothelial Cells ◽

Lymphoid Tissue ◽

Intraepithelial Lymphocytes ◽

Germinal Centers ◽

Lymphoid Tissues ◽

Electron Microscopic ◽

Upper Eyelid ◽

Antigen Uptake ◽

Bordetella Avium

Conjunctiva-associated lymphoid tissue (CALT) was characterized in normal and Bordetella avium-infected turkey poults during the first 5 weeks of life. At 1, 5, 12, 19, 25, and 33 days post-hatching (DPH), upper and lower eyelids were examined by gross, histologic, and electron microscopic techniques. CALT was confined to the proximal part of the lower eyelid near the conjunctival fornix; it appeared by 5 DPH as individual lymphoid nodules and as dense masses by 19 DPH. In the upper eyelid, CALT was present only as isolated nodules. Histologically. CALT was composed of dense lymphocyte infiltrates within subepithelial connective tissue, intraepithelial lymphocytes, and flattened lymphoid-associated epithelium that lacked goblet cells. Germinal centers were in CALT by 19 DPH. By scanning electron microscopy, epithelial cells over lymphoid areas were flat and had short, irregular microvilli; non-lymphoid areas were covered by cells with tall, regular microvilli. Transmission electron microscopy revealed that with increasing age of birds, the epithelium over conjunctival lymphoid infiltrates became progressively flattened and infiltrated by lymphocytes. Some blood vessels in CALT had high endothelial cells; lymphocytes were in the lumen and between or beneath endothelial cells. In B. avium- infected poults. CALT was increased, developed earlier, and contained more germinal centers than in normal poults. We conclude that CALT of turkeys closely resembles other mucosal lymphoid tissues and may serve as a site for local antigen uptake.

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Recirculation and homing of lymphocyte subsets: dual homing specificity of beta 7-integrin(high)-lymphocytes in nonobese diabetic mice

Blood ◽

10.1182/blood.v88.3.934.bloodjournal883934 ◽

1996 ◽

Vol 88 (3) ◽

pp. 934-944

Author(s):

A Hanninen ◽

M Salmi ◽

O Simell ◽

D Andrew ◽

S Jalkanen

Keyword(s):

Immune System ◽

Nod Mice ◽

Intraepithelial Lymphocytes ◽

Mucosal Immune System ◽

Lymphoid Tissues ◽

Integrin Subunit ◽

Homing Receptor ◽

Functional Studies ◽

Peripheral Lymph ◽

Nonobese Diabetic Mice

The beta 7-integrin subunit can pair with two alpha-chains, alpha 4 and alpha E, and is expressed mainly on lymphocytes. As an alpha 4- heterodimer it binds to the mucosal addressin MAdCAM-1, thus acting as a mucosal homing receptor. As an alpha E-heterodimer it binds to E- cadherin and is mainly found on intestinal intraepithelial lymphocytes. Consequently, beta 7 is mostly expressed on lymphocytes of the mucosal immune system. To study the compartmentalization of these cells further we compared the distribution of such lymphocytes in two strains of mice (BALB/c and NOD) and found that the distribution of beta 7-positive lymphocytes among various lymphoid tissues in these strains was very different. In NOD mice a conspicuous population of beta 7- integrin(high) lymphocytes expressing either alpha 4, alpha E, or both, was found in nonmucosal lymphoid tissues such as peripheral lymph nodes (PLNs). They mostly expressed the PLN homing receptor L-selectin, and included both naive and memory cells on the basis of their expression of CD44/pgp-1 and CD45RB, as did the few beta 7(high) lymphocytes in BALB/c PLNs. Their homing to Peyer's patches (PPs) and PLNs was equally effective and the cells homing to PPs and PLNs were equal in their level of L-selectin and alpha 4/beta 7 expression. However, functional studies indicated that their homing to PPs mostly depended on alpha 4/beta 7-integrin, whereas they mainly used L-selectin to home to PLNs. beta 7(high) lymphocytes were found also in circulating blood of unmanipulated NOD mice, and their L-selectin expression was higher than in BALB/c mice. These results show that lymphocytes of the mucosal immune system may also express the peripheral node homing receptor L- selectin during their recirculation and that in NOD mice they frequently retain a dual homing specificity, which leads to their accumulation in nonmucosal tissues.

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Experimental transmission and pathogenesis of immunodeficiency syndrome in cats

Blood ◽

10.1182/blood.v70.6.1880.bloodjournal7061880 ◽

1987 ◽

Vol 70 (6) ◽

pp. 1880-1892

Author(s):

EA Hoover ◽

JI Mullins ◽

SL Quackenbush ◽

PW Gasper

Keyword(s):

Viral Replication ◽

Opportunistic Infections ◽

Feline Leukemia Virus ◽

In Vivo Model ◽

Lymphoid Tissues ◽

Experimental Transmission ◽

Lymphoid Follicles ◽

Immunodeficiency Disease ◽

Immunodeficiency Syndrome

We describe the identification, experimental transmission, and pathogenesis of a naturally occurring powerfully immunosuppressive isolate of feline leukemia virus (designated here as FeLV-FAIDS) which induces fatal acquired immunodeficiency syndrome (AIDS) in 100% (25 of 25) of persistently viremic experimentally infected specific pathogen- free (SPF) cats after predictable survival periods ranging from less than 3 months (acute immunodeficiency syndrome) to greater than one year (chronic immunodeficiency syndrome), depending on the age of the cat at time of virus exposure. The pathogenesis of FeLV-FAIDS-induced feline immunodeficiency disease is characterized by: a prodromal period of largely asymptomatic viremia; progressive weight loss, lymphoid hyperplasia associated with viral replication in lymphoid follicles, lymphoid depletion associated with extinction of viral replication in lymphoid follicles, intractable diarrhea associated with necrosis of intestinal crypt epithelium, lymphopenia, suppressed lymphocyte blastogenesis, impaired cutaneous allograft rejection, hypogammaglobulinemia, and opportunistic infections such as bacterial respiratory disease and necrotizing stomatitis. The clinical onset of immunodeficiency syndrome correlates with the replication of a specific FeLV-FAIDS viral variant, detected principally as unintegrated viral DNA, in bone marrow, lymphoid tissues, and intestine. Two of seven cats with chronic immunodeficiency disease that survived greater than 1 year after inoculation developed lymphoma affecting the marrow, intestine, spleen, and mesenteric nodes. Experimentally induced feline immunodeficiency syndrome, therefore, is a rapid and consistent in vivo model for prospective studies of the viral genetic determinants, pathogenesis, prevention, and therapy of retrovirus-induced immunodeficiency disease.

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CD8 T Cells Are Required for the Formation of Ectopic Germinal Centers in Rheumatoid Synovitis

Journal of Experimental Medicine ◽

10.1084/jem.20011565 ◽

2002 ◽

Vol 195 (10) ◽

pp. 1325-1336 ◽

Cited By ~ 100

Author(s):

Young Mo Kang ◽

Xiaoyu Zhang ◽

Ulf G. Wagner ◽

Hongyu Yang ◽

Robert D. Beckenbaugh ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Structural Integrity ◽

Cell Receptor ◽

Cd40 Ligand ◽

Lymphoid Tissues ◽

Mantle Zone ◽

Lymphoid Follicles ◽

Ifn Γ ◽

Immunohistochemical Studies

The assembly of inflammatory lesions in rheumatoid arthritis is highly regulated and typically leads to the formation of lymphoid follicles with germinal center (GC) reactions. We used microdissection of such extranodal follicles to analyze the colonizing T cells. Although the repertoire of follicular T cells was diverse, a subset of T cell receptor (TCR) sequences was detected in multiple independent follicles and not in interfollicular zones, suggesting recognition of a common antigen. Unexpectedly, the majority of shared TCR sequences were from CD8 T cells that were highly enriched in the synovium and present in low numbers in the periphery. To examine their role in extranodal GC reactions, CD8 T cells were depleted in human synovium-SCID mouse chimeras. Depletion of synovial CD8 T cells caused disintegration of the GC-containing follicles. In the absence of CD8 T cells, follicular dendritic cells disappeared, production of lymphotoxin-α1β2 markedly decreased, and immunoglobulin (Ig) secretion ceased. Immunohistochemical studies demonstrated that these CD8 T cells accumulated at the edge of the mantle zone. Besides their unique localization, they were characterized by the production of interferon (IFN)-γ, lack of the pore-forming enzyme perforin, and expression of CD40 ligand. Perifollicular IFN-γ+ CD8 T cells were rare in secondary lymphoid tissues but accounted for the majority of IFN-γ+ cells in synovial infiltrates. We propose that CD8+ T cells regulate the structural integrity and functional activity of GCs in ectopic lymphoid follicles.

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Intestinal epithelial cell-derived interleukin-7: a mechanism for the alteration of intraepithelial lymphocytes in a mouse model of total parenteral nutrition

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00192.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. G84-G91 ◽

Cited By ~ 18

Author(s):

Hua Yang ◽

Xiaoyi Sun ◽

Emir Q. Haxhija ◽

Daniel H. Teitelbaum

Keyword(s):

Parenteral Nutrition ◽

Total Parenteral Nutrition ◽

Critical Factor ◽

Intraepithelial Lymphocytes ◽

Control Group ◽

Lymphoid Tissues ◽

Intestinal Epithelial ◽

Crystalloid Solution ◽

Interleukin 7 ◽

Ad Libitum Feeding

Total parenteral nutrition (TPN), with the absence of enteral nutrition, results in profound changes to both intestinal epithelial cells (EC) as well as the adjacent intraepithelial lymphocyte (IEL) population. Intestinal EC are a rich source of IL-7, a critical factor to support the maintenance of several lymphoid tissues, and TPN results in marked EC changes. On this basis, we hypothesized that TPN would diminish EC-derived IL-7 expression and that this would contribute to the observed changes in the IEL population. Mice received enteral food and intravenous crystalloid solution (control group) or TPN. TPN administration significantly decreased EC-derived IL-7 expression, along with significant changes in IEL phenotype; decreased IEL proliferation; and resulted in a marked decrease in IEL numbers. To better determine the relevance of TPN-related changes in IL-7, TPN mice supplemented with exogenous IL-7 or mice allowed ad libitum feeding and treated with exogenous administration of anti-IL-7 receptor (IL-7R) antibody were also studied. Exogenous IL-7 administration in TPN mice significantly attenuated TPN-associated IEL changes, whereas blocking IL-7R in normal mice resulted in several similar changes in IEL to those observed with TPN. These findings suggest that a decrease in EC-derived IL-7 expression may be a contributing mechanism to account for the observed TPN-associated IEL changes.

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