Immunological Organ Research Articles

Innate immunity mediated by epidermal keratinocytes promotes acquired immunity involving Langerhans cells and T cells in the skin

Skin is an immunological organ consisting of epidermal cells, i.e. keratinocytes and Langerhans cells (LCs, antigen-presenting dendritic cells), and both innate and acquired immune systems operate upon exposure of the skin to various external microbes or their elements. To explore the relationship between innate and acquired immunities in the skin, we investigated whether Toll-like receptor (TLR) ligation of epidermal cells enhances the ability of LCs to present a specific antigen to T cells in mice. LC-containing epidermal cells were incubated with CpG oligonucleotide (TLR9 ligand) modified with trinitrophenyl hapten, and cultured with hapten-primed CD4(+) T cells. TLR9 ligand was capable of enhancing the hapten-presenting ability of LCs when LC-enriched epidermal cells, but not purified LCs, were used as the LC source, suggesting that bystander keratinocytes play a role in the enhancement of LC function. Cultivation of freshly isolated epidermal cells with CpG promoted the expression of major histocompatibility complex (MHC) class II and CD86 molecules on LCs. CpG enhanced the production of interleukin (IL)-1alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor (TNF)-alpha by primarily cultured keratinocytes. The addition of a cocktail of neutralizing antibodies against these cytokines abrogated the CpG-promoted, antigen-presenting ability of LC-enriched epidermal cells. Moreover, the addition of culture supernatants from CpG-stimulated keratinocytes restored the ability of purified LCs. Our study demonstrated that although the direct effect of CpG on LCs is minimal, LC function can be up-regulated indirectly by cytokines released by CpG-stimulated keratinocytes. This also implies that innate immunity evoked by TLR ligation of keratinocytes enhances acquired immunity comprising LCs and T cells.

The Effects of Fumonisin B1 on viability and mitogenic response of avian immune cells

Fumonisin B1 (FB1) is a mycotoxin produced by the fungus Fusarium verticillioides (formerly Fusarium moniliforme) and is found in diverse crops such as corn, wheat, and barley. Many diseases linked to FB1, such as porcine pulmonary edema, rat hepatic cancer, and equine leukoencephalomalacia, indicate a compromised immune system. The purpose of this study was to determine whether FB1 altered immunological responses in various cell populations of Single Comb White Leghorn chicks. Cells collected for this study were obtained from those immunological organs with well-defined responses (i.e., spleen, thymus, and blood). Cell populations were exposed to 5 to 50 µg/mL FB1 in vitro for 24 to 72 h, and viability and mitogenic response were evaluated. The effects of FB1 on the mitogenic response were evaluated in cell populations from the spleen and blood stimulated with the mitogens, lipopolysaccharide, concanavalin A, and pokeweed mitogen and in thymocytes stimulated with concanavalin A. The 3-(4,5-dimethylthazol-2-yl)-diphenyl-2H-tetrazolium bromide (MTT) reduction assay was used to assess viability and mitogenic response. Fumonisin B1 decreased spleen cell viability and mitogenic response, albeit the degree of decrease varied with mitogen and time of exposure. Fumonisin B1 increased number of viable thymic cells at 50 µg/mL but had no effect on the mitogenic response of thymocytes. Fumonisin B1 had no effect on blood lymphocyte viability or mitogenic response.

1140915445 Increased numbers of FoxP3+ cells in vaginal mucus from normal pregnant mice suggest early antigen‐specific tolerance mechanism during pregnancy

The fetal survival within the maternal uterus is thought to be due to a transient immunological tolerance, being CD4+CD25+ T regulatory cells (Tregs) crucial players. Former studies confirmed diminished total numbers of this unique population in abortion‐prone mice (DBA/2J‐mated CBA/J females) as compared to a control with normal pregnancy outcome (BALB/c‐mated CBA/J females) and suggested that Tregs act in an antigen‐specific fashion. This hypothesis led us to investigate the kinetics of Tregs during pregnancy (day 0, 2, 5, 8, 10 or 12 of pregnancy) in abortion‐prone mice and the control group. Our data confirmed diminished number of Tregs in immunological relevant organs such as lymph nodes and thymus within the abortion‐prone mice. The enormous augmentation in the number of FoxP3+ cells in vaginal mucus already on day 0.5 after conception, followed by increased Tregs levels at early pregnancy stages, suggest, that Tregs need to be activated by male antigens for being protective. Notably, the abortion‐prone mice displayed again a lower total amount of Tregs as compared to the control. Similar progesterone levels in spite of different pregnancy outcome reinforce the theory of antigen specificity of pregnancy‐induced Tregs. The antigen presentation would take place in the periphery e.g. in vaginal mucus, the first site of contact with paternal antigens, directly after insemination. Interestingly the transfer of Tregs from normal pregnant mice at this time point prevented fetal rejection. Our results suggest the crucial role of Tregs already shortly after conception.

Obesity and Diabetes

Obesity and Diabetes

The Liver as an Immunological Organ

The liver is a unique anatomical and immunological site in which antigen-rich blood from the gastrointestinal tract is pressed through a network of sinusoids and scanned by antigen-presenting cells and lymphocytes. The liver's lymphocyte population is selectively enriched in natural killer and natural killer T cells which play critical roles in first line immune defense against invading pathogens, modulation of liver injury and recruitment of circulating lymphocytes. Circulating lymphocytes come in close contact to antigens displayed by endothelial cells, Kupffer cells and liver resident dendritic cells in the sinusoids. Circulating lymphocytes can also contact hepatocytes directly, because the sinusoidal endothelium is fenestrated and lacks a basement membrane. This unique anatomy of the liver may facilitate direct or indirect priming of lymphocytes, modulate the immune response to hepatotrophic pathogens and contribute to some of the unique immunological properties of this organ, particularly its capacity to induce antigen-specific tolerance.

The larynx as an immunological organ: immunological architecture in the pig as a large animal model.

The larynx is a mucosal organ positioned at the divergence of the respiratory and digestive tracts. It is exposed to a wide variety of environmental components, including foreign antigens, tobacco smoke, laryngopharyngeal reflux and pollutants. The mucosal immune system generates either active immune responses or tolerance, depending on the nature of the antigen and we hypothesize that the larynx is important organ for immunological decision-making in the airway. Because the pig is an ideal large animal model in which to explore laryngological research questions, such as those relating to laryngeal transplantation, we investigated the normal mucosal immunology of the porcine larynx. Pig larynges and tracheae were processed and prepared for bright-field microscopy and quantitative, multiple-colour immunofluorescence histology using pig-specific monoclonal antibodies. There was an abundance of immunologically active cells within the mucosa of the larynx and trachea of both the newborn and adult animal. Specifically, major histocompatibility complex class II (MHC class II+) cells, CD4+ and CD8+ cells were identified, although regional differences in numbers were apparent: specifically, the supraglottis contained fewer immunologically relevant cells than other sites sampled. There was a significant correlation between the numbers of MHC class II+ and CD4+ cells indicating co-ordinate regulation and therefore functional local interactions. The presence of such an immunological structure suggests that the larynx may have important functions in respiratory immunology and that it may trigger strong alloresponses after laryngeal transplantation.

Skin Barrier Dysfunction and Systemic Sensitization to Allergens Through the Skin

Most allergic, atopic and hypersensitive reactions are associated with Th2-biased immune responses and allergen-specific IgE antibodies. Pathological allergic disorders are on an alarming increase in the industrialized world. Understanding the mechanism of primary sensitization to allergens is important in elucidating the pathogenesis of these diseases and for possibly preventing their development. In this article, we review recent information supporting that epidermal allergen exposure may contribute to systemic allergic diseases and that atopy may be secondary to skin barrier dysfunction in some dermatoses. The skin is an active immunological organ, which functions as a primary defence and biosensor to the external environment. The critical permeability barrier function is mediated by the outmost layer of the epidermis, the stratum corneum. Perturbation of the stratum corneum initiates a chain of event, which activates homeostatic responses in the underlying epidermis. Repeated barrier-disruption, whether environmentally or genetically determined, may however stimulate signaling cascades that lead to inflammation and epidermal hyperplasia. Skin barrier dysfunction may also allow entry of allergens, which can lead to primary systemic sensitization. The altered epidermal microenvironment in barrier-disrupted skin appears to be particularly well suited for the induction of potent Th2-type responses with production of allergen-specific IgE. Epidermal exposure to food antigens can prevent the normal induction of oral tolerance and also lead to airway eosinophilia following inhalation. Exposure to allergens on barrier-disrupted skin may as such serve as a natural sensitization pathway for food allergy and respiratory allergic disease.

Eustachian tube possesses immunological characteristics as a mucosal effector site and responds to P6 outer membrane protein of nontypeable Haemophilus influenzae

The eustachian tube (ET) plays an important role in the pathogenesis of otitis media (OM). To better understand its biology and to develop a nasal vaccine for preventing OM, mucosal lymphocytes in the ET were analyzed, and the ET's immunological function was investigated. Mononuclear cells were isolated from murine ET, and lymphocyte subsets were analyzed by flow cytometry. Antibody-producing cells were determined by enzyme-linked immunospot assay. The expression of cytokine mRNA in ET CD4 + T cells was determined by RT-PCR. Results in naive mice showed that the ET contained many immunocompetent cells, including a relative large number of IgA-producing cells and Th2 cytokine-expressing T cells. Next, we investigated antigen-specific immune responses in the ET. Mice were immunized intranasally with the P6 outer membrane of nontypeable Haemophilus influenzae (NTHi) and cholera toxin (CT), and P6-specific immune responses in the ET were examined. P6-specific IgA producing cells markedly increased in the ET. Moreover, in vitro stimulation with P6 of purified CD4 + T cells from immunized mice resulted in the proliferation of CD4 + T cells that expressed Th2 cytokine mRNA. These results indicate that the ET might be characterized as a mucosal effector site and that antigen-specific IgA and Th2 immune responses could be induced in the ET by intranasal immunization. These findings suggest that the ET might be a key immunological organ in the pathogenesis of OM, and in the development of a nasal vaccine.

Histology, Immunohistochemistry and Ultrastructure of the Equine Palatine Tonsil

The palatine tonsils of five young horses formed 10-12 cm elongated follicular structures extending from the root of the tongue on either side to the base of the epiglottis and lateral to the glossoepiglottic fold. The stratified squamous non-keratinized epithelium of the outer surface was modified into crypts as reticular epithelium by heavy infiltration of lymphoid cells from underlying lymphoid follicles. In places, lymphoid tissue reaching almost to the surface and with only one to two cell layers intact was identified as the lymphoepithelium. Langerhans cells with Birbeck granules were interspersed between epithelial cells. Lymphoid tissue organized in lymphoid follicles constituted the parenchyma of the palatine tonsil. CD4-positive cells were more numerous and CD8-positive lymphocytes less numerous compared with their distribution in the lingual tonsil. B cells and macrophages were also more numerous than in the lingual tonsil and lectins showed a different pattern of attachment. M cells were not observed. High endothelial venules with well-developed vesiculo-vacuolar organelle had structural evidence of transendothelial and interendothelial migration of lymphocytes. Striated muscles as seen in the deeper lamina propria mucosae of the lingual tonsil were absent. The immunohistological and ultrastructural characteristics of the equine palatine tonsil are similar to those of humans but differ from those of the lingual tonsil and are consistent with a role as an effector and inductor immunological organ.

Novel immunoglobulin-like transcripts in teleost fish encode polymorphic receptors with cytoplasmic ITAM or ITIM and a new structural Ig domain similar to the natural cytotoxicity receptor NKp44

Members of the immunoglobulin superfamily (IgSF) include a group of innate immune receptors located in the leukocyte receptor complex (LRC) and other small clusters such as the TREM/NKp44 cluster. These receptors are characterised by the presence of immunoglobulin domains, a stalk, a transmembrane domain, and a cytoplasmic region containing either an immunoreceptor tyrosine-based inhibitory motif (ITIM) or are linked to an adapter molecule with an activation motif (ITAM) for downstream signalling. We have isolated two carp cDNA sequences encoding receptors in which the extracellular Ig domain structurally resembles the novel V-type Ig domain of NKp44. This is supported by a homology model. The cytoplasmic regions contain either an ITAM (Cyca-NILT1) or ITIMs (Cyca-NILT2). The tissue expression of these receptors is nearly identical, with the highest expression in the immunological organs. Peripheral blood leucocytes showed no detectable expression, but upon in vitro culture expressed NILT1, the activating receptor, and not the inhibitory NILT2 receptor. Southern blot analysis indicated that the NILT1 and NILT2 sequences belong to a multigene family. Analysis of the NILT Ig domain-encoding sequences amplified from both genomic DNA and cDNA revealed extensive haplotypic and allelic polymorphism. Database mining of the zebrafish genome identified several homologs on Chromosome 1, which also contains a cluster of class I major histocompatibility genes. This constellation is reminiscent of the TREM/NKp44 gene cluster and the HLA complex located on human Chromosome 6. The carp NILT genes form a unique cluster of innate immune receptors, which are highly polymorphic, and characterised by a new Ig structural subfamily and are distinct from the novel immune-type receptors (Nitrs) found in other fish species.

Somatostatin receptors and autoimmune‐mediated diabetes

Somatostatin (SST) peptide is produced by various SST-secreting cells throughout the body and acts as a neurotransmitter or paracrine/autocrine regulator in response to ions, nutrients, peptides hormones and neurotransmitters. SST is also widely distributed in the periphery to regulate the inflammatory and immune cells in response to hormones, growth factors, cytokines and other secretive molecules. SST peptides are considered the most important physiologic regulator of the islet cell, gastrointestinal cell and immune cell functions, and the importance of SST production levels has been implicated in several diseases including diabetes. The expression of SST receptors has also been found in T lymphocytes and primary immunologic organs. Interaction of SST and its receptors is also involved in T-cell proliferation and thymocyte selection. SSTR gene-ablated mice developed diabetes with morphologic, physiologic and immunologic alterations in the endocrine pancreas. Increased levels of mononuclear cell infiltration of the islets are associated with the increased levels of antigen-presenting cells located in the islets and peripancreatic lymph nodes. Increased levels of SST were also found in antigen-presenting cells and are associated with a significant increase of CD8 expression levels on CD4(+)/CD8(+) immature thymocytes. These findings highlight the crucial role of this neuroendocrine peptide and its receptors in regulating autoimmune functions.

The liver as an immunological organ

Abstract The liver is an immunologically distinct organ that contains its own unique population of cells of the innate and adaptive cellular immune response. The liver is known as a site of inflammatory immune responses as well as a site of tolerance induction. This dual function is important to understand the pathogenesis of infectious liver diseases and to understand induction of tolerance upon exposure to oral and allograft antigens. This review will address the unique role of the liver in the immune system.

Histology of selected immunological organs in polar bear ( Ursus maritimus) from East Greenland in relation to concentrations of organohalogen contaminants

Samples of lymph nodes (axillary, n=54 and inguinal, n=45), spleen ( n=60), thymus ( n=11) and thyroid tissue ( n=5) from a total of 82 polar bears ( Ursus maritimus) collected in East Greenland 1999–2002 were examined histologically. The purpose was to relate histology to concentrations of organohalogen contaminants (OHCs) [i.e., sum (Σ)PCBs, ΣDDTs, ΣHCHs, ΣCHLs, HCB, Dieldrin and ΣPBDEs] determined in adipose tissue, as studies on polar bears have indicated that some OHCs act as immunosuppressive agents. Secondary follicle counts were evaluated in spleen and lymph nodes, and semiquantitively divided into four groups (0: few/absent to 3: high). In the spleen, a high secondary follicle count was found in 21% of the cases (12/60), and this was significantly higher in subadults ( p<0.01) compared to adults of both sexes. Also in the lymph nodes a high secondary follicle count was found in 20% of the cases (20/99), and in the axillary lymph nodes changes were significantly higher in subadults ( p<0.05) compared to adults of both sexes. Significantly weak correlations between concentrations of OHCs and the amount of secondary follicles in lymph nodes was found, but probably occurred as a consequence of other multiple stress factor(s) (all: p<0.05) and also one significant, but modest positive correlation was found between ΣPBDE concentrations and secondary follicle counts ( p<0.01; r=0.41). In spleen, a significant relation between low concentrations of OHCs in adipose tissue and few/absent secondary follicles was found with respect to ΣCHLs, ΣHCHs, HCB and Dieldrin. No histopathological observations (e.g., neoplasia) were found in spleen or lymph nodes, nor in thymus or thyroid. In conclusion, the present data suggest that the exposure concentrations of OHCs to polar bears are unlikely to have resulted in adverse effects on the tissues in question, although ΣCHLs, ΣHCHs, HCB and Dieldrin were related to increased secondary follicle counts in the spleen.

Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response.

The skin is an important immunological organ with an outer protective layer, the stratum corneum forming a barrier between the skin-associated lymphoid tissue and the environment. We show that gently removing the stratum corneum with adhesive tape permits potent epicutaneous immunization to protein antigens. IL-4 secretion by T cells from draining lymph nodes and high levels of specific IgE and IgG1 with no IgG2a showed that the immune responses induced following epicutaneous antigen exposure are strongly Th2 biased. Similar responses were obtained with different antigens and mouse strains. In contrast, subcutaneous immunization with antigen delivery into the dermis was less potent and gave predominantly Th1 responses. Removal of the stratum corneum increased expression of MHC class II, CD86, CD40, CD54 and CD11c on Langerhans cells, but did not cause them to migrate. Rapid migration from epidermis to draining lymph node was obtained, however, by exposure to antigen after removal of the stratum corneum, suggesting that maturation and migration of Langerhans cells are independently regulated events. These results suggest that antigen presentation by Langerhans cells gives predominantly Th2 responses. This may provide an explanation for allergic sensitization to some antigens. It may also be a useful non-invasive, non-adjuvant-dependent method of vaccination.

Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response

Rationale The skin is an important immunological organ which is naturally exposed to a variety of environmental agents including allergens. The current study investigated the systemic effects of epicutaneous exposure to high molecular-weight proteins and allergens. Methods Ear skin of BALB/c mice was gently abraded with adhesive tape prior to application of peanut protein or ovalbumin. Immunity was investigated by studying specific T cell proliferation, cytokine secretion and immunoglobulin production. Epicutaneous immunization was compared to subcutaneous immunization. Skin immunity was explored by studying Langerhans cell (LC) maturation and migration. Results Abrasion of the skin allows potent epicutaneous immunization to protein antigens. High levels of antigen-specific IL-4, IgE and IgG1 with no IgG2a showed that the responses are strongly Th2 biased. Subcutaneous immunization was less potent and gave predominantly Th1 responses. Primary epicutaneous immunization changed responses elicited by subcutaneous antigen in complete Freunds adjuvant from Th1 to Th2. Additionally, epicutaneous immunization converted an existing antigen-specific Th1 response to a Th2 response, indicating dominance of the skin-induced immunity. Abrasion of the skin increased expression of MHC class II, CD86, CD40, CD54 and CD11c on LCs but did not cause migration. Rapid migration from epidermis to draining lymph node was observed only after skin abrasion and exposure to antigen, suggesting that maturation and migration of LCs are independently regulated events. Conclusions These results suggest that protein antigen presentation by LCs favors Th2 responses. This may provide an explanation for allergic sensitization to some antigens. It may also be a useful non-invasive, non-adjuvant-dependent method of vaccination.

Current status of bacterial translocation as a cause of surgical sepsis

In recent years it has been increasingly recognized that the gastrointestinal tract has functions other than simply the digestion and excretion of foodstuffs. The gut is also a metabolic and immunological organ that serves as a barrier against living organisms and antigens within its lumen. This role is termed ‘gut barrier function’. The fact that luminal contents in the caecum have a bacterial concentration of the order of 10 organisms per millilitre of faeces, whilst portal blood and mesenteric lymph nodes are usually sterile, dramatically illustrates the efficacy of this barrier function. The idea that the alimentary tract, teeming with its own bacterial flora, could represent a source of sepsis under certain conditions has interested clinicians for many years. This theory, usually referred to as the ‘gut origin of sepsis’ hypothesis, is not new. In the late nineteenth century, the idea developed that peritonitis could result from the passage of bacteria from organs adjacent to the peritoneal cavity. In Germany this was referred to as durchwanderungs-peritonitis, literally translated as ‘wandering through peritonitis’. In 1891 and 1895, two separate investigators hypothesized that viable bacteria could pass through the intact gut wall in vivo. These findings were confirmed after the Second World War by Fine and colleagues who were able to detect viable bacteria in the peritoneal cavity of dogs in a haemorrhagic shock model. Schatten et al. demonstrated that bacteria could migrate from the gastrointestinal tract into the portal circulation in the absence of an infective process in humans. Subsequently it has become clear that, in addition to Gram-negative bacteria, endotoxin, Gram-positive bacteria and fungi can pass through the mucosal barrier. In 1979, Berg and Garlington defined this phenomenon as ‘bacterial translocation’. The term ‘bacterial translocation’ is used to describe the passage of viable resident bacteria from the gastrointestinal tract to normally sterile tissues such as the mesenteric lymph nodes and other internal organs. The term also applies to the passage of inert particles and other macromolecules, such as lipopolysaccharide endotoxin, across the intestinal mucosal barrier. Accepted: November 1, 2004

Principles of Immunology

The immune system, composed of innate and acquired immunity, allows an organism to fight off foreign pathogens. Healthy immunity accomplishes four essential principles: (1) ability to detect and fight off infection; (2) ability to recognize a host's own cells as "self," thereby protecting them from attack; (3) a memory from previous foreign infections; and (4) ability to limit the response after the pathogen has been removed. In an unaltered state, the intricate network of immunologic organs and cells creates an environment for proper host defense. Without adequate execution of immunologic mechanisms, a host is rendered defenseless against pathogens. Conversely, an unchecked immune response can be self-destructive. As a result of either of these untoward sequelae, immune dysfunction can elicit disease states in the host. The goal of this review is to elucidate the characteristics of a healthy immune system, focusing on the principles of immunity and the cells that participate in host protection. We also briefly discuss the clinical ramifications of immune dysfunction.

Long-lasting donor passenger leukocytes after hepatic and intestinal transplantation in rats

Background: Donor passenger leukocytes (DPLs) that migrate after organ transplantation stimulate the recipient immune system and normally cause rejection and graft vs. host reaction. However, DPLs also contribute to the unresponsiveness to the donor organ. The quantity and quality of these migrating cells are considered dependent on individual transplanted organs. We compared the DPLs of the liver, which might contain somatic stem cells, with those of intestinal grafts that have highly immunogenetic cells. To study DPLs over a long period, we used green fluorescent protein (GFP) transgenic (Tg) rats developed by us as donors. Methods: We performed orthotopic liver transplantation (OLT) and small bowel transplantation (SBT) from GFP Tg rats to wild recipients. A short course of tacrolimus (0.64 mg/kg, intramuscularly) was used to prevent antigenicity of the GFP. The fate of the DPLs in the peripheral blood and the recipient bone marrow was monitored by flow cytometry. Using long-surviving recipients, the GFP + cells in the graft and various host immunologic organs were measured and characterized by immunohistochemical staining. Results: In both groups, the numbers of the GFP + cells in the peripheral blood increased transiently and then gradually decreased to undetectable levels. While no GFP + cells were identified in the long-surviving-recipient bone marrow, there were a few GFP + cells in the graft liver, graft mesenteric lymph nodes and the recipient spleen. These cells showed major histocompatibility complex (MHC) class II antigen. There was no significant difference in the migration patterns of the GFP + cells in the OLT and SBT rats. Conclusions: In both the OLT and SBT groups, the DPLs migrated transiently in the recipient peripheral blood. A small numbers of MHC class II-positive DPLs were present at the graft site and in the host spleen, but not in the bone marrow. There were no significant differences in the migration patterns of the DPLs between the OLT and SBT rats over the long term.

IgE and non-IgE food allergy

Food allergy (FA) is characterized by an abnormal immunologic reactivity to food proteins. The gastro-intestinal tract serves not only a nutritive function but also is a major immunologic organ. Although previously thought to be triggered primarily by an IgE-mediated mechanism of injury, considerable evidence now suggests that non-IgE mechanisms may also be involved in the pathogenesis of FA. To review the immunologic disturbances that occur in FA and to correlate these with the clinical manifestations expressed in affected target organs based upon a classification of IgE and non-IgE mechanisms. Data collected from a computerized MEDLINE search were used for the analysis of the following topics: immediate GI hypersensitivity, oral allergy syndrome, acute urticaria and angioedema, acute bronchospasm, celiac disease, cow's milk enteropathy, dietary protein enterocolitis, breast milk colitis, proctolitis, proctitis, dermatitis herpetiformis, Heiner syndrome, eosinophilic gastroenteritis, atopic dermatitis, asthma, attention-deficit-hyperactivity disorder and behavioral disorders, as well as systems affected by mucosal associated lymphoid tissue-mediated injury of associated lymphoid tissues and the immunologic deviation to Th1 or Th2 mechanisms of FA. The results of this review allow the construction of a central, unifying hypothesis for a new classification of FA as follows: the clinical manifestations of FA, expressed in affected target organs, may be the result of immunologic injury mediated by interaction of food antigens with contiguous elements of mucosal associated lymphoid tissue. These appear to be modulated by relative imbalances of the Th1/Th2 paradigm, which may be the ultimate determinant governing the expression of FA as IgE-mediated, non--IgE-mediated, or mixed forms of IgE/non-IgE mechanisms of FA.

Pulmonary appendix of the short-tailed shrew (Blarina): a unique immunologic organ.

The right bronchus of the short-tailed shrew, Blarina brevicauda, terminates in a nonrespiratory pulmonary appendix (PA) containing two bronchial extensions. The experimentally demonstrated ability of these structures to collect and peristaltically expel aspirated material was initially assumed to be a sufficient reason for their developmental persistence, but as bronchus associated lymphoid tissue (BALT) became a subject of immunologic interest in other species, a possible immunologic role for the concentrations of BALT observed in the shrew PA were investigated. As the BALT of the PA contained many well-differentiated plasma cells and numerous particle-containing macrophages, 6-mu paraffin sections were treated with an immunoperoxidase avidin-biotin preparation that chromogenically identified alpha chains of IgA in many of the PA plasma cells and their associated luminal secretions. Also, vascular injections revealed that the PA had a complex relationship with anastomotic sinusoids connecting the bronchial and pulmonary circulation systems, and scanning electron microscopy showed that the luminal epithelial surfaces of the PA were virtually identical to the scattered BALT aggregates in the bronchi of other animals. It thus appeared that these unique structures in the shrew are morphologically and topographically suited to receive aspirated antigens that induce secretory IgA production, while possibly providing other humoral and cellular immunologic products to the general circulation.