Aging impacts isolated lymphoid follicle fevelopment and function

Background  

Immunosenescence is the age-related decline and dysfunction of protective immunity leading to a marked increase in the risk of infections, autoimmune disease, and cancer. The majority of studies have focused on immunosenescence in the systemic immune system; information concerning the effect of aging on intestinal immunity is limited. Isolated lymphoid follicles (ILFs) are newly appreciated dynamic intestinal lymphoid structures that arise from nascent lymphoid tissues, or cryptopatches (CP), in response to local inflammatory stimuli. ILFs promote "homeostatic" responses including the production of antigen-specific IgA, thus playing a key role in mucosal immune protection. ILF dysfunction with aging could contribute to immunosenescence of the mucosal system, and accordingly we examined phenotypic and functional aspects of ILFs from young (2 month old) and aged (2 year old) mice.     

Reappraisal of histogenesis in the bursal lymphoid follicle of the chicken.

The development of the bursal follicle and the appearance of the follicle-associated epithelial (FAE) cell and the reticuloepithelial (REp) cell were studied. The stages of development of the bursal follicle were observed by light and electron microscopy; an anticytokeratin monoclonal antibody was also used. At the beginning of follicle development, a mesenchymal cell cluster is observed in the tunica propria; the cluster becomes wedged in a niche of the surface epithelium, and gradually it is completely surrounded by the epithelium itself, which closes under the clump of mesenchymal cells. The epithelial cells lying upon the mesenchymal clump become necrotic, and a number of mesenchymal cells bulge out, forming the FAE cells. The epithelial cells that have closed under the mesenchymal nodule become stratified and form the REp cells; they become star-shaped because the medullary-lymphoid cells grow between them. Finally, the cortex is formed, possibly as a result of the migration of medullary cells before they peripheralize. It is concluded that FAE cells are not specialized epithelial cells, as they do not react to an anticytokeratin monoclonal antibody; on the contrary, they are formed by mesenchymal stemcells that bulge into the lumen and change their character after moving into the epithelium. The REp cells appear in the follicular primordium shortly after the bursal follicle begins to develop; the pronounced reactivity of the REp cells to an anticytokeratin monoclonal antibody supports the hypothesis of their epithelial origin.     

Role of secreted conjunctival mucosal cytokine and chemokine proteins in different stages of trachomatous disease

Background

Chlamydia trachomatis is responsible for trachoma, the primary cause of preventable blindness worldwide. Plans to eradicate trachoma using the World Health Organization''s SAFE program (Surgery, Antibiotics, Facial Cleanliness and Environment Improvement) have resulted in recurrence of infection and disease following cessation of treatment in many endemic countries, suggesting the need for a vaccine to control infection and trachomatous disease. Vaccine development requires, in part, knowledge of the mucosal host immune responses in both healthy and trachomatous conjuctivae—an area of research that remains insufficiently studied.

Methodology/Principal Findings

We characterized 25 secreted cytokines and chemokines from the conjunctival mucosa of individuals residing in a trachoma endemic region of Nepal using Luminex X100 multiplexing technology. Immunomodulating effects of concurrent C. trachomatis infection were also examined. We found that proinflammatory cytokines IL-1β (r = 0.259, P = 0.001) and TNFα (r = 0.168, P<0.05) were significantly associated with trachomatous disease and concurrent C. trachomatis infection compared with age and sex matched controls from the same region who did not have trachoma. In support of these findings, anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) was negatively associated with chronic scarring trachoma (r = −0.249, P = 0.001). Additional cytokines (Th1, IL-12p40 [r = −0.212, P<0.01], and Th2, IL-4 and IL-13 [r = −0.165 and −0.189, respectively, P<0.05 for both]) were negatively associated with chronic scarring trachoma, suggesting a protective role. Conversely, a pathogenic role for the Th3/Tr1 cytokine IL-10 (r = 0.180, P<0.05) was evident with increased levels for all trachoma grades. New risk factors for chronic scarring trachoma included IL-6 and IL-15 (r = 0.259 and 0.292, respectively, P<0.005 for both) with increased levels for concurrent C. trachomatis infections (r = 0.206, P<0.05, and r = 0.304, P<0.005, respectively). Chemokine protein levels for CCL11 (Eotaxin), CXCL8 (IL-8), CXCL9 (MIG), and CCL2 (MCP-1) were elevated in chronic scarring trachoma compared with age and sex matched controls (P<0.05, for all).

Conclusions/Significance

Our quantitative detection of previously uncharacterized and partially characterized cytokines, a soluble cytokine receptor, and chemokines for each trachoma grade and associations with C. trachomatis infections provide, to date, the most comprehensive immunologic evaluation of trachoma. These findings highlight novel pathologic and protective factors involved in trachomatous disease, which will aid in designing immunomodulating therapeutics and a vaccine.     

Murine isolated lymphoid follicles contain follicular B lymphocytes with a mucosal phenotype

Isolated lymphoid follicles (ILFs) are organized intestinal lymphoid structures whose formation can be induced by luminal stimuli. ILFs have been demonstrated to act as inductive sites for the generation of immune responses directed toward luminal stimuli; however, the phenotype of the immune response initiated within ILFs has largely been uninvestigated. To gain a better understanding of the immune responses initiated within ILFs, we examined phenotypic and functional aspects of the largest cellular component of the murine ILF lymphocyte population, B lymphocytes. We observed that murine ILF B lymphocytes are composed of a relatively homogenous population of follicular B-2 B lymphocytes. Consistent with their proximity to multiple stimuli, ILF B lymphocytes displayed a more activated phenotype compared with their counterparts in the spleen and Peyer's patch (PP). ILF B lymphocytes also expressed higher levels of immunomodulatory B7 and CD28 family members B7X and programmed death-1 compared with their counterparts in the spleen and PP. ILF B lymphocytes preferentially differentiate into IgA-producing plasma cells and produce more IL-4 and IL-10 and less interferon-gamma compared with their counterparts in the spleen. Immunoglobulin repertoire analysis from individual ILFs demonstrated that ILFs contain a polyclonal population of B lymphocytes. These findings indicate that murine ILFs contain a polyclonal population of follicular B-2 B lymphocytes with a phenotype similar to PP B lymphocytes and that, in unchallenged animals, ILFs promote immune responses with a homeostatic phenotype.     

Generation and characterization of monoclonal antibodies recognizing follicle epithelial M cells in rabbit gut-associated lymphoid tissues

A panel of mouse B cell hybridomas producing monoclonal antibodies (mAb) directed against rabbit M cell-containing epithelia was developed. By immunohistochemistry, the mAb 5D9, 5B11, 1D9, and 4G2 were found to label approximately 50% of the follicle-associated epithelial (FAE) cell populations overlying lymphoid follicles in Peyer's patches, cecal patch, sacculus rotundus, and appendix. The cell staining was localized to FAE cell basolateral surfaces outlining the M cell pockets which enclosed clusters of mononuclear leukocytes, and extended from the crypts of Peyer's patches and sacculus rotundus, and appendiceal crevices, to the apices of domes. In contrast, the stem cell and proliferative regions facing the lamina propria were devoid of immunologically reactive sites. The mAb 5D9, 1D9, and 4G2 did not recognize antigens associated with non-FAE cells in the intestinal lymphoid tissues examined. Only the mAb 5B11 labeled apical surfaces of Peyer's patch and cecal patch non-FAE. However, this mAb did not label interdomal colonic epithelial cells in sacculus rotundus and appendix. Besides recognizing FAE cells, the mAb 4G2 recognized a cross-reactive antigen displayed by dome and lymphoid follicle lymphocytes. By flow cytometry, the mAb 5D9, 5B11, and 1D9 were shown to stain from 14 to 29% of the cells in M cell-enriched populations prepared from Peyer's patches, sacculus rotundus, and appendix, whereas mAb 4G2 was found to recognize 44-54% of the cells. Two-color flow cytometric analysis showed that the mAb stained a functionally distinct subpopulation of Peyer's patch phagocytic cells and did not recognize spleen macrophages. These findings indicate that the panel of mAb recognized novel antigens expressed by FAE cells overlying intestinal lymphoid aggregates, and that the mAb allow identification of phagocytic M cells in suspensions of FAE cells.     

Helicobacter pylori (H. pylori) molecular signature in conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma

Conjunctival mucosa-associated lymphoid tissue (MALT) lymphoma is an extranodal marginal zone B-cell lymphoma that is characterized by an exaggerated clonal expansion of B cells, which implicate a pathological proliferative response to antigen(s) including bacteria. Helicobacter pylori (H. pylori) infection is recognized as one of the causative agents of gastric MALT lymphoma; however, it has not been reported in extra gastric MALT lymphoma. We studied 5 patients (4 adults and 1 child) with salmon-colored conjunctival lesions. One patient also had a history of abnormal bone marrow biopsy a year earlier with lymphoid aggregates involving 5% of the overall bone marrow. The conjunctival lesions of the 5 patients were biopsied. Histopathological diagnoses were consistent with conjunctival MALT lymphoma. Lymphoma and normal conjunctival cells were microdissected using laser capture microscopy or manual techniques. DNA was extracted and subjected to PCR amplification using H. pylori gene-specific primers from the urease B and vac/m2 gene. Cells from chronic conjunctivitis (normal lymphocytes), conjunctival human T-cell lymphotropic virus type-1/adult T-cell leukemia/lymphoma (HTLV-1/ATL), and orbital B-cell lymphoma were also microdissected, processed and analyzed. PCR amplification and Southern blot hybridization demonstrated H. pylori DNA in the conjunctival MALT lymphoma cells of 4/5 cases. The negative case was the one with a history of abnormal bone marrow. In contrast, H. pylori gene was not detected in normal conjunctival cells from the cases of MALT lymphoma or the lymphocytes, ATL and orbital B-lymphoma cells from the controls. These data suggest that H. pylori may play a role in conjunctival MALT lymphoma.     

Ecological immunology: The organism in context

A major challenge in integrative biology is understanding the mechanisms by which organisms regulate trade-offs among various functions competing for limiting resources. Key among these competing processes is the maintenance of health and the production of offspring. Optimizing both, given limited resources, can prove challenging. The physiological and behavioral changes that occur during reproduction have been shown to greatly influence an organism's immune system, which can have consequences for susceptibility to disease. Likewise, investing in costly immunological defenses can impair reproductive function. However, the precise nature of these physiological and behavioral interactions appears to be greatly dependent upon the environmental context in which they occur. Here we take a comparative look at interactions between the reproductive and immune systems, including current immunological approaches, and discuss how similar studies can reveal vastly disparate results. Specifically, we highlight results from the ornate tree lizard (Urosuarus ornatus) and the Siberian hamster (Phodopus sungorus) model systems, which provide an example of current research in the field. Collectively, these results emphasize the importance of resource availability and an individual's energy stores for the existence of life-history trade-offs and the efficiency of physiological processes in general. Akin to Dobzhansky's famous line, like other aspects of biology, nothing in ecoimmunology seems to make sense except in the context of an organism's environment.     

The immunology of South-American blastomycosis

Conclusions The immunological study of South-American blastomycosis, like in other deep mycoses, is very important. It permits the diagnosis of infection without disease as shown in the epidemiological surveys.Only after the immunological study by the serological reactions we had the indication that a clinical cure most of times does not represent a real cure of the patient, and by the interruption of treatment the relapses do occur.The relapses do occur also in patients under treatment and sometimes they are revealed only by the serological tests.The serological tests can indicate a good response of the patient to the treatment, and we think that they are the best criteria of cure when they become negative.By the serological follow up it is possible to have an idea about the prognosis of a patient. But, perhaps, this would be accomplished better in a study correlating the serological and skin tests which has not yet been done.The studies on the immunology of South-American blastomycosis were aided partially by a grant of the Fundação de Amparo à Pesquisa do Estado São Paulo.