Formation Of Lymphoid Structures Research Articles

Morphofunctional changes in the lymphoid component of the rats prostate gland in conditions of immunostimulation

To date, the state of the local immune system of the human prostate gland is not sufficiently studied, which prevents in-depth study of sexual disorders and infertility in men, as well as its common diseases: hypertrophy, adenoma, cancer. In order to study the morphological state of the lymphoid apparatus of the prostate of rats on the background of immunostimulation, 60 rat prostate glands were studied by histological, morphometric and statistical methods. Using the methods of variation statistics, we assessed the correctness of the distribution of signs for each of the obtained variation series, the average values for each attribute that was studied, standard errors and standard deviations. The reliability of differences in values between independent micrometric values with a normal distribution of signs was determined by the Student’s criterion. The paper describes the patterns of formation of the local immune system of the prostate gland in the experiment after the introduction of immunoglobulin in adult male rats Wistar line. It was revealed that in rats after administration of immunoglobulin, the formation of lymphoid structures was observed three days earlier than in intact and control rats. First appear lymphoid formations in the stroma of the prostate gland, in the blood vessels – perivascular lymphoid nodules. By the end of the first week, lymphoid structures are formed in the glandular epithelium of the prostate gland – lymphoepithelial nodules. In lymphoid structures, the content of lymphocytes in all periods exceeds the benchmarks with the maximum changes on day 7 of the study. Reactive changes in the capillary endothelium in close relationship with the restructuring of lymphoid nodules during antigenic stimulation indicate that they are redundant in providing immune homeostasis. Thus, against the background of immunostimulation, changes occur in the local immune system of the prostate gland, manifested in an increase in the number of immunocompetent cells, the formation of lymphoid nodules, and are accompanied by corresponding changes in the hemomicrocirculatory bed.

Radioprotective Properties of Neomitilan in Experimental Radiation Pneumonia.

The efficiency of neomitilan, a polysaccharide isolated from Crenomytilus grayanus mussels, was studied in experimental model of radiation pneumonia (irradiation of the animal lungs with a total dose of 14 and 28 Gy). Histological study showed that an increase in the number of nucleated components in the lungs of animals subjected to neomitilan inhalation prior to irradiation. Proliferation of bronchial epitheliocytes and the formation of additional lymphoid structures were also revealed in these animals. The absence of a tendency to lung tissue recovery in animals irradiated with 28 Gy is due to extreme radiation toxicity.

A Major Hindrance in Antibody Affinity Maturation Investigation: We Never Succeeded in Falsifying the Hypothesis of Single-Step Selection

Antibody (Ab) affinity maturation (AAM) referred originally to the observed increase in average Ab affinity against a hapten (1). Later, it was found that AAM is associated with the formation of transient lymphoid structures in the B cell zones of lymphoid tissues, called germinal centers (GC), during T-cell dependent immune responses in higher vertebrates (2). In another line of research, AAM was related to the occurrence of mutations in the variable (V) domain of Ab heavy (H) and light (L) chains, respectively, VH and VL. In those works, a mutational analysis of Ab V genes was performed, initially on bulk splenic plasma B cells and later on GC B cells vs. extrafollicular B cells, after successive immunizations. The results showed typically an increased number of mutated GC B cells (3–6), and an accumulation of mutations per Ab chain during the ongoing immune response, with many mutated B cells displaying higher affinity for the hapten used for immunization. This provided strong support to a previously suggested concept (7), according to which AAM is a B-cell receptor (BCR)-based Darwinian evolutionary process. A few years later, two complementary hypotheses were proposed. The first one, based on a mathematical model, suggested that, for the fastest production of high affinity Abs, the mutation rate in GC B cells should be minimal before GCs reach a threshold size, and then switch abruptly to the maximal possible rate (8). The second hypothesis proposed, for the assumed Darwinian process, alternating cycles of B cell proliferation plus mutation plus selection (9). These ideas were soon extended in another modeling work, showing that Ab affinity can be maximized when the mutational mechanism switches on and off regularly (10). These results contributed considerably to strengthen the general belief in the recycling or multiple-step selection hypothesis. On the other hand, more recently, alternative B cell selection mechanisms were proposed that do not require multiple-step selection in order to be compatible with observed levels of Ab affinity increase during a primary immune response (11, 12). There is still much to learn about AAM mechanisms (13–17), and there is a need to clarify some aspects of the GC physiology where overinterpretation and preconceptions prevail (18, 19). The multiple-step selection hypothesis is a prominent example of a concept that, having important basic and practical implications, has never been confirmed. Clearly, a direct way to establish it would be to observe multiple BCR-mediated selection events by tracking individual B cells via imaging of lymphatic tissue, observing SHM taking place between selection rounds. However, direct observation of even one selection event is not yet possible. At the same time, attempts to interpret indirect data must be faulty due to the need to use unverified assumptions on AAM mechanisms. Therefore, we take here a radically different approach: we propose to consider the single-step selection concept to be a null-hypothesis which should be attempted to be falsified (Figure ​(Figure1).1). Because this ansatz puts the focus on a process of random non-directed acquisition of mutations, it minimizes the need for unverified assumptions. And because mutations carry the signature of the selection process, the data to be used should consist of Ab V gene sequences. In the following, we examine two possible falsifying strategies. Figure 1 Sketch of proliferation plus SHM and selection history of a plasma or memory cell. (A) Single-step selection. Several cell division plus mutation cycles and a single final selection step before terminal differentiation into a plasma or memory cell. (B) ... Falsifying the Null-Hypothesis with Phylogenetic Trees Let us consider all mutated VH or VL sequences belonging to a given B cell lineage. The corresponding phylogenetic tree is a result of the evolutionary process undergone by the initial sequence, and as such, is shaped by the various factors pertaining to the affinity maturation process. Extensive work was performed on developing methods to build phylogenetic trees from V genes of a common lineage (20) and to analyze how shape measures depend on AAM mechanisms (21, 22). These simulations show that the tree shapes vary most on the initial clone affinity and the selection threshold, and much less in dependence on the rates of GC B cell recycling (22), not allowing for a unique mapping from tree shapes to selection mechanisms – likely because the investigated trees were small. In addition to global measures not always being helpful in pointing to mechanisms at the micro-evolutionary scale (15, 23, 24), simulation of global measures like peak total GC B cell numbers did not lead to results that contradict the single-step hypothesis (22). Summing up, the null-hypothesis has never been falsified by examining the shapes of phylogenetic trees.

Blocking lymphotoxin: a potential therapy for diabetes?

Nonobese diabetic (NOD) mice spontaneously develop autoimmune diabetes, bearing close resemblance to the human condition. The disease is mediated by auto-specific T cells, which infiltrate the pancreatic islets and destroy insulin-producing β cells. A hallmark of the disease is the de novo generation of lymph-node-like structures in the pancreas, which are essential for progression of the disease. A large body of evidence implicates lymphotoxin (LT) in the formation of these lymphoid structures and the production of follicular dendritic cells. In support of this notion, the ectopic expression of LT can result in the in situ generation of lymph-node-like organs in the periphery. Hence, it was supposed that the formation of organized lymphoid structures in the pancreas of NOD mice might be regulated by LT.

“Lymphoid” chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjögren's syndrome patients: Possible participation in lymphoid structure formation

“Lymphoid” chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjögren's syndrome patients: Possible participation in lymphoid structure formation

"Lymphoid" chemokine messenger RNA expression by epithelial cells in the chronic inflammatory lesion of the salivary glands of Sjögren's syndrome patients: possible participation in lymphoid structure formation.

Many studies have shown that the microanatomic organization of infiltrating leukocytes in the salivary gland lesions of patients with Sjögren's syndrome (SS) resembles the structure of lymphoid organs. A newly defined set of chemokines referred to as "lymphoid," which orchestrate leukocyte microenvironmental homing and contribute to the formation of lymphoid structures, provides directional clues. The aim of this study was to investigate the possible existence of "lymphoid" chemokines in the chronic inflammatory lesions of SS patients and thus validate their potential involvement in the disease process. Twelve patients with primary SS, 3 patients with secondary SS, 4 patients with other autoimmune disorders, and 4 control individuals were the subjects of this study. Reverse transcriptase-polymerase chain reaction analysis was performed in order to examine the messenger RNA (mRNA) expression of "lymphoid" chemokines. Furthermore, in situ hybridization studies revealed chemokine mRNA localization. Immunohistochemistry was also applied in order to identify the cell types that expressed the chemokine mRNA. STCP-1/monocyte-derived chemokine and TARC mRNA were expressed in the majority of patients with primary and secondary SS, in 2 of 4 patients with other autoimmune disorders, and in 2 of 4 controls. BCA-1, ELC, and PARC mRNA were only detected in patients with primary and secondary SS. SLC mRNA was also detected in 1 non-SS patient. The main cellular sources of chemokine mRNA were ductal epithelial cells and infiltrating mononuclear leukocytes. The expression pattern of "lymphoid" chemokine mRNA points further to the role of epithelial cells in the pathogenesis of SS and offers new insight into the potential mechanisms that could be involved in leukocyte attraction and in the in situ formation of secondary lymphoid tissue structures.

Role of dendritic cells in the induction and maintenance of autoimmune diseases.

Autoimmune diseases are characterised by the loss of tolerance against self-determinants, activation of autoreactive lymphocytes and pathological damage to single or multiple organs. The mechanisms by which autoimmune responses are triggered and activation of autoreactive lymphocytes is initiated and maintained are not yet fully understood. Translocation of previously immunologically ignored antigens from the periphery to secondary lymphoid organs is probably a key step in the initiation of autoimmunity. Antigen transport and primary sensitisation of T lymphocytes is mainly mediated by dendritic cells which reside in peripheral non-lymphoid tissues and maintain a continuous gradient of antigens towards secondary lymphoid tissues. In the transgenic rat insulin promoter-glycoprotein model of autoimmune diabetes, dendritic cell (DC)-mediated antigen transport initiates an autoimmune response against a pancreatic neoself-antigen. Dose and timing of antigen delivery by DC and turnover of antigenic peptides presented by DC are the main parameters regulating the outcome of autoimmune diabetes in this model system. An important sequel of continued antigenic stimulation via DC is the formation of lymphoid structures in the pancreas. Thus, appropriate and repeated activation of cytotoxic T lymphocytes by DC, in concert with local inflammatory processes leading to formation of organised lymphoid tissue in the target organ, is likely to be crucial in the development of destructive autoimmunity. Therapeutic intervention to selectively manipulate antigen transport by dendritic cells or to influence antigen presentation may prove beneficial for the treatment of autoimmune diseases. Furthermore, the capacity of DC to induce potent antiself responses might have implications for the use of DC presenting self-antigens in treatment of established tumours.