2.2 Organs, tissues, and general structures
In higher vertebrates, the immune system consists of primary (lymphocyte-generating) and secondary (immune response-generating) lymphoid organs. The fetal liver, thymus and bone marrow constitute the primary lymphoid organs, while the spleen, lymph nodes, and mucosal-associated lymphoid tissue (MALT) comprise the secondary lymphoid organs.
Fish organization of immune organs is slightly different from higher vertebrates. The main difference is that fish lack bone marrow and lymph nodes and the primary lymphoid organs are the thymus, the head kidney, or pronephros for teleosts, and the Leydig and epigonal organs for chondrichthyes, while secondary lymphoid organs are the spleen, the kidney, and MALT present in peripheral immune tissues (Figure 2.3).
pronephros 전신
Figure 2.3 Schematic representation of the hematopoietic tissues of the three main fish groups and types of lymphoid cells described for each group.
Whether jawless fish have dedicated primary lymphohematopoietic organs is unknown, but several discrete structures have been found in different phases of their development, including the typhlosole (an invagination of the intestinal epithelium), the nephric fold, the supraneural body, and a thymus-like lymphoepithelial structure, termed thymoids, located in the tips of the gill filaments and secondary lamellae of lamprey larvae (Amemiya et al., 2007; Bajoghli et al., 2011). Jawless fish lymphocytes (L), differentiated from hematopoietic stem cells (HSC), bear the variable lymphocyte receptors, in which the basic rearranging element is a leucine-rich repeat cassette, either VLRA or VLRB.
Chondrichthyes and Osteichthyes lymphocyte receptor system is based in the presence of variable receptors of the Ig superfamily, either BCR or TCR.
The BCR isotypes found in Chondrichthyes are three heavy chains (IgH) and four light chains (IgL), while Osteichthyes have three IgH and three IgL chains. T cells in Chondrichthyes can be ab or gd, and no CD4 or the cytokine system associated to T helper cells has been found to date (Venkatesh et al., 2014).
In bony fish, ab T cells can differentiate into CD8+ T cytotoxic cells and CD4+ T helper cells.
2.2.1 Primary lymphoid organs
2.2.1.1 The thymus The thymus is the primary organ for functional T lymphocyte development and is present in all jawed vertebrates, but not completely defined in the jawless fish.
Cartilaginous fish are the first in evolution to possess a thymus originating from pharyngeal pouches. The structure of the organ is similar to its mammalian counterparts, with a differentiated cortex and medulla and expression of Rag1 (recombination activating gene) and TdT (recombination of terminal deoxyribonucleotidyl transferase) molecules, which are involved in the rearrangement and recombination of B and T cell receptors (Criscitiello et al., 2010; Wyffels et al., 2005; Zapata, 1981).
The teleost thymus gland can be uni-, bi-, or trilobed, depending on the species and is situated on the dorsolateral region of the gill chamber. The structure varies from one species to another, but a cortex/medulla architecture is always apparent (Chilmonczyk, 1992; Zapata and Amemiya, 2000). The thymus is comprised of two main populations of cells: the thymic epithelial cells and the lymphoid thymocytes (mainly T cells).
Additional cells include the surrounding mesenchymal cells that together with the thymic epithelial cells form an epithelial environmental niche for the support of T cell differentiation. Comparative studies on thymus development performed in mice (Mus musculus) and zebrafish (Danio rerio) indicate that this process is highly conserved throughout vertebrate evolution and many of the mechanisms and transcription factors involved in this development are common among species (Ma et al., 2013b). The age-related involution process, which characterizes this organ in higher vertebrates, is not as accused in most fish species; however, thymic growth and function may be modulated by crucial factors like aging, sexual maturity, or stress.
2.2.1.2 The kidney
The equivalent to mammalian bone marrow in elasmobranchs is the Leydig organ (nested between the muscular tissue and the mucosa of the esophagus) and the epigonal organ (associated with the gonads).
In teleosts, the kidney is the main hematopoietic organ, and, in some species like zebrafish, it is associated with the dorsal aorta to form the “whole-kidney marrow” (Traver et al., 2003).
dorsal aorta 등대동맥
The fish kidney is a complex organ composed of four structurally and functionally distinct systems, including the hematopoietic, reticulo-endothelial, endocrine, and secretory systems. It is commonly located ventrally across the backbone, extending from the base of the cranium along the body axis.
hematopoietic system 조혈계
reticulo-endothelial system 세망내피계
endocrine system 내분비계
secretory immune system 분비면역계
The anterior portion of the kidney (defined as anterior kidney, pronephros, or head kidney) is usually bifurcated into two lobes, lacks nephrons, and has no renal function.
It houses the main hematopoietic site, and is interdigitated with some adrenal-like endocrine tissue. On the other hand, the posterior kidney possesses a combination of both renal and immune tissue (Grassi Milano et al., 1997; Zapata et al., 1995).
adrenal-like endocrine tissue 부신 유사 내분비 조직
posterior kidney 후부신장
B cell development in hematopoietic organs is believed to occur in specialized domains or niches that are spatially separated from environments supporting development of other hematopoietic cell types such as erythroid and myeloid cells.
niche 틈새
erythroid cell 적혈구
myeloid cell 골수세포
Structurally, the pronephros is supported by a connective tissue capsule and a network of reticular fibers that holds the parenchyma, and is dispersed through an extensive system of sinusoids. Melano-macrophage centers that are formed by totally or partially encapsulated accumulations of pigment-containing macrophages are distributed randomly throughout the lymphohematopoietic tissue.
pronephros 전신
reticular fiber 그물섬유
parenchyma 유조직
Melano macrophage 멜라닌 대식세포
accumulation 축적
A special organization of B cell maturation within the kidney has been reported in rainbow trout (Oncorhynchus mykiss). In this species, the anterior kidney is thought to mostly contain proliferating B cell precursors and plasma cells, whereas the posterior kidney houses B cells in different states of activation and plasmablast/plasma cells (both antigen-secreting cells, but in different maturation stages).
A model for B cell development, differentiation, and distribution was consequently proposed for teleosts. Early B cell development is harbored in the anterior kidney, from where the mature naïve B cells can be distributed via the blood to the spleen and posterior kidney. The activation by an antigen can lead to the plasmablast stage and even further to the more mature plasma cell that can be relocated in a niche of the anterior kidney to become long-lived (Ye et al., 2011a; Zwollo et al., 2008).
2.2.2 Secondary lymphoid organs
2.2.2.1 The spleen
The spleen is a compact, dark red organ located in the peritoneal cavity. Elasmobranchii are compartmentalized into discrete vascularized T cell and B cell zones, although no detectable marginal zone separates red pulp from white pulp (Rumfelt et al., 2002).
peritoneal cavity 복강
Elasmobranchii 판새아강(연골어류의 일종)
compartmentalize 구분하다
discrete 별개의
vascularize 혈관을 발달시키다, <기관·조직에> 혈관을 지나가게 하다
Teleost spleen structure is similar to the mammalian structure, with blood vessels and differentiated red pulp and white pulp; however, the white pulp is poorly developed. It is surrounded by a fibrous capsule from where small trabeculae extend into the parenchyma.
differentiate 구별하다
The red pulp occupies the majority of the organ and consists of a reticular cell network that supports blood sinusoids and leukocytes, mainly macrophages and lymphocytes. The white pulp is mainly composed of ellipsoids (terminal capillaries) that have a thin endothelial layer, surrounded by fibrous reticulum and accumulations of macrophages.
reticular cell 망상세포
terminal capillary 종말모세혈관
This part is also rich in melanomacrophage centers. The functions of the spleen are numerous, including blood filtration, erythrocytic destruction, antigen presentation, and antibody production (Zapata, 1982; Zapata et al., 1995).
2.2.2.2 Mucosal-associated lymphoid tissues (MALT)
Fish leukocytes are not only present in immune organs, but have been described in practically all fish tissues, including liver, digestive tract, gills, skin, and gonads (Abos et al., 2013; Ballesteros et al., 2013a; Chaves-Pozo et al., 2003). While in some tissues like liver or gonad there is a spare distribution of leukocytes, more organized structures are found in mucosal tissues such as gut, gills, and skin.
Consequently, these structures are usually designated as gut-associated lymphoid tissue (GALT), gill-associated lymphoid tissue (GIALT), and skin-associated lymphoid tissue (SALT).
Because the specific composition and functionality of these tissues will be extensively reviewed in successive chapters, we will only name their most important characteristics. The GALT in fish comprises B and T lymphocytes both in the lamina propria (LP) and as intraepithelial lymphocytes (IEL); however, a singular characteristic of the fish GALT is the absence of organized structures like Peyer’s patches and mesenteric lymph nodes present in mammals (Rombout et al., 2011).
Although many studies have characterized different aspects of the immune response of the teleost gut in response to diverse pathogens or stimuli (reviewed in Rombout et al., 2011), most studies have focused on the posterior segments exclusively. Recently, it has been revealed that other segments of the digestive tract have numerous leukocyte populations that effectively respond to infection or oral vaccination.
For example, in rainbow trout, both B and T lymphocytes are recruited to the pyloric caeca region in response to local viral stimuli (Ballesteros et al., 2013a, 2013b). Regarding GIALT, fish have been long known to possess all types of leukocytes dispersed within the gill lamellae. In addition, a novel immune structure was recently described in salmonids in association to gills.
pyloric caeca 유문수
This structure, designated as interbranchial lymphoid tissue (ILT), is mainly composed of T cells embedded in a meshwork of epithelial cells (Haugarvoll et al., 2008; Koppang et al., 2010). The morphological differences between the thymus and the ILT suggest different roles in the salmonid immune system. Furthermore, the absence of Rag transcription in gills appears to indicate that this tissue would function as a secondary immune organ, even though its specific role in defense has not been elucidated (Koppang et al., 2010).
Due to its lack of keratinization, teleost skin has living epithelial cells in direct contact with the water. Consequently, mucous secretions are produced by different types of epithelial cells, those located in the superficial layer in particular. Furthermore, specific unicellular glands in the skin of gnathostome fish are the goblet cells, the sacciform cells, and the club cells (Zaccone et al., 2001). Additionally, the skin epidermis contains multiple B and T cells that have shown to respond to pathogens in different species (Findly et al., 2013; Jorgensen et al., 2009; Xu et al., 2013).
keratinization 각질화