Lymphoid Cells and Organs Evolutionary Comparisons

While innate systems of immunity are seen in invertebrates and even in plants, the evolution of lymphoid cells and organs evolved only in the phylum Vertebrata. Consequently, adaptive immunity, which is mediated by antibodies and T cells, is only seen in this phylum. However, as shown in Figure 2-23, the kinds of lymphoid tissues seen in different orders of vertebrates differ.

As one considers the spectrum from the earliest vertebrates, the jawless fishes (Agnatha), to the birds and mammals, evolution has added organs and tissues with immune

Kidney Thymus / GALT

GALT

GALT

Kidney Thymus / GALT

Spleen

Thymus GALT

Lamprey

Spleen

Trout

Spleen

Thymus GALT

Frog

Thymus

Spleen

Bone marrow

Thymus

Aves Lymph Nodes

Bone marrow

Thymus

GALT

Lymph nodes

Bone marrow

Frog

Chicken

Thymus

GALT

Peyer's patch

Spleen

Bone marrow

Mouse

Lymph nodes

Peyer's patch

Spleen

Bone marrow

Mouse

GALT

Thymus

Spleen

Bone marrow

Lymph nodes

Germinal centers

Teleostei

Anura

Aves

Mammalia

Anura

Aves

Lymph Chains
Osteichthyes Osteichthyes

Agnatha Gnathostomata

Vertebrata

FIGURE 2-23

Evolutionary distribution of lymphoid tissues. The presence and location of lymphoid tissues in several major orders of vertebrates are shown. Although they are not shown in the diagram, cartilaginous fish such as sharks and rays have GALT, thymus, and a spleen. Reptiles also have GALT, thymus, and spleen and they also may have lymph nodes that participate in immunological reactions. Whether bone marrow is involved in the generation of lymphocytes in reptiles is under investigation. [Adapted from Dupasquier and M. Flajnik, 1999. In Fundamental Immunology 4th ed., W. E. Paul, ed., Lippincott-Raven, Philadelphia.]

functions but has tended to retain those evolved by earlier orders. While all have gut-associated lymphoid tissue (GALT) and most have some version of a spleen and thymus, not all have blood-cell-forming bone marrow or lymph nodes, and the ability to form germinal centers is not shared by all. The differences seen at the level of organs and tissues are also reflected at the cellular level. Lymphocytes that express antigen-specific receptors on their surfaces are necessary to mount an adaptive immune response. So far, it has not been possible to demonstrate the presence of T or B lymphocytes in the jawless fishes, and attempts to demonstrate an adaptive immune response in lampreys and hagfish, members of the order Agnatha, have failed. In fact, only jawed vertebrates (Gnathosomata), of which the cartilaginous fish (sharks, rays) are the earliest example, have B and T lymphocytes and support adaptive immune responses.

SUMMARY

■ The cells that participate in the immune response are white blood cells, or leukocytes. The lymphocyte is the only cell to possess the immunologic attributes of specificity, diversity, memory, and self/nonself recognition.

■ Many of the body's cells, tissues, and organs arise from the progeny of different stem-cell populations. The division of a stem cell can result in the production of another stem cell and a differentiated cell of a specific type or group.

■ All leukocytes develop from a common multipotent hematopoietic stem cell during hematopoiesis. Various hematopoietic growth factors (cytokines) induce proliferation and differentiation of the different blood cells. The differentiation of stem cells into different cell types requires the expression of different lineage-determining genes. A number of transcription factors play important roles in this regard.

■ Hematopoiesis is closely regulated to assure steady-state levels of each of the different types of blood cell. Cell division and differentiation of each of the lineages is balanced by programmed cell death.

■ There are three types of lymphocytes: B cells, T cells, and natural killer cells (NK cells). NK cells are much less abundant than B and T cells, and most lack a receptor that is specific for a particular antigen. However, a subtype of NK cells, NK1-T cells, have both T-cell receptors and many of the markers characteristic of NK cells. The three types of lymphoid cells are best distinguished on the basis of function and the presence of various membrane molecules.

■ Naive B and T lymphocytes (those that have not encountered antigen) are small resting cells in the G0 phase of the cell cycle. After interacting with antigen, these cells enlarge into lymphoblasts that proliferate and eventually differentiate into effector cells and memory cells.

■ Macrophages and neutrophils are specialized for the phagocytosis and degradation of antigens (see Figure 2-9).

Phagocytosis is facilitated by opsonins such as antibody, which increase the attachment of antigen to the membrane of the phagocyte.

■ Activated macrophages secrete various factors that regulate the development of the adaptive immune response and mediate inflammation (see Table 2-7). Macrophages also process and present antigen bound to class II MHC molecules, which can then be recognized by TH cells.

■ Basophils and mast cells are nonphagocytic cells that release a variety of pharmacologically active substances and play important roles in allergic reactions.

■ Dendritic cells capture antigen. With the exception of follicular dendritic cells, these cells express high levels of class II MHC molecules. Along with macrophages and B cells, dendritic cells play an important role in TH-cell activation by processing and presenting antigen bound to class II MHC molecules and by providing the required co-stimulatory signal. Follicular dendritic cells, unlike the others, facilitate B-cell activation but play no role in T-cell activation.

■ The primary lymphoid organs provide sites where lymphocytes mature and become antigenically committed. T lymphocytes mature within the thymus, and B lymphocytes arise and mature within the bone marrow of humans, mice, and several other animals, but not all vertebrates.

■ Primary lymphoid organs are also places of selection where many lymphocytes that react with self antigens are eliminated. Furthermore, the thymus eliminates thymo-cytes that would mature into useless T cells because their T-cell receptors are unable to recognize self-MHC.

■ The lymphatic system collects fluid that accumulates in tissue spaces and returns this fluid to the circulation via the left subclavian vein. It also delivers antigens to the lymph nodes, which interrupt the course of lymphatic vessels.

■ Secondary lymphoid organs capture antigens and provide sites where lymphocytes become activated by interaction with antigens. Activated lymphocytes undergo clonal proliferation and differentiation into effector cells.

■ There are several types of secondary lymphoid tissue: lymph nodes, spleen, the loose clusters of follicles, and Peyer's patches of the intestine, and cutaneous-associated lymphoid tissue. Lymph nodes trap antigen from lymph, spleen traps blood-borne antigens, intestinal-associated lymphoid tissues (as well as other secondary lymphoid tissues) interact with antigens that enter the body from the gastrointestinal tract, and cutaneous-associated lymphoid tissue protects epithelial tissues.

■ An infection that begins in one area of the body eventually involves cells, organs, and tissues that may be distant from the site of pathogen invasion. Antigen from distant sites can arrive at lymph nodes via lymph and dendritic cells, thereby assuring activation of T cells and B cells and release of these cells and their products to the circulation. Inflammatory processes bring lymphocytes and other leukocytes to the site of infection. Thus, although dispersed through out the body, the components of the immune system communicate and collaborate to produce an effective response to infection.

■ Vertebrate orders differ greatly in the kinds of lymphoid organs, tissues, and cells they possess. The most primitive vertebrates, the jawless fishes, have only gut-associated lymphoid tissues, lack B and T cells, and cannot mount adaptive immune responses. Jawed vertebrates possess a greater variety of lymphoid tissues, have B and T cells, and display adaptive immunity.

References

Appelbaum, F. R. 1996. Hematopoietic stem cell transplantation. In Scientific American Medicine. D. Dale and D. Feder-man, eds. Scientific American Publishers, New York.

Banchereau J., F. Briere, C. Caux, J. Davoust, S. Lebecque, Y. J. Liu, B. Pulendran, and K. Palucka. 2000. Immunobiology of dendritic cells. Annu. Rev. Immunology. 18:767.

Bendelac, A., M. N. Rivera, S-H. Park, and J. H. Roark. 1997. Mouse CD1-specific NK1 T cells: Development, specificity and function. Annu. Rev. Immunol. 15:535.

Clevers, H. C., and R. Grosschedl. 1996. Transcriptional control of lymphoid development: lessons from gene targeting. Immunol. Today 17:336.

Cory, S. 1995. Regulation of lymphocyte survival by the BCL-2 gene family. Annu. Rev. Immunol. 12:513.

Ganz, T., and R. I. Lehrer. 1998. Antimicrobial peptides of vertebrates. Curr. Opin. Immunol. 10:41.

Liu, Y. J. 2001. Dendritic cell subsets and lineages, and their functions in innate and adaptive immunity. Cell 106:259.

Melchers, F., and A. Rolink. 1999. B-lymphocyte development and biology. In Fundamental Immunology, 4th ed., W. E. Paul, ed., p. 183. Lippincott-Raven, Philadelphia.

Nathan, C., and M. U. Shiloh. 2000. Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens. Proc. Natl. Acad. Sci. 97:8841.

Pedersen, R. A. 1999. Embryonic stem cells for medicine. Sci. Am. 280:68.

Osborne, B. A. 1996. Apoptosis and the maintenance of home-ostasis in the immune system. Curr. Opin. Immunol. 8:245.

Picker, L. J., and M. H. Siegelman. 1999. Lymphoid tissues and organs. In Fundamental Immunology, 4th ed., W. E. Paul, ed., p. 145. Lippincott-Raven, Philadelphia.

Rothenberg, E. V. 2000. Stepwise specification of lymphocyte developmental lineages. Current Opin. Gen. Dev. 10:370.

Ward, A. C., D. M. Loeb, A. A. Soede-Bobok, I. P. Touw, and A. D. Friedman. 2000. Regulation of granulopoiesis by transcription factors and cytokine signals. Leukemia 14:973.

Weissman, I. L. 2000. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287:1442.

http://www.ncbi.nlm.nih.gov/prow

The PROW Guides are authoritative short, structured reviews on proteins and protein families that bring together the most relevant information on each molecule into a single document of standardized format.

http://hms.medweb.harvard.edu/nmw/HS_heme/ AtlasTOC.htm

This brilliantly illustrated atlas of normal and abnormal blood cells informatively displayed as stained cell smears has been assembled to help train medical students at the Harvard Medical School to recognize and remember cell morphology that is associated with many different pathologies, including leukemias, anemias, and even malarial infections.

http://www.nih.gov/news/stemcell/primer.htm

This site provides a brief, but informative introduction to stem cells, including their importance and promise as tools for research and therapy.

http://www.nih.gov/news/stemcell/scireport.htm

A well written and comprehensive presentation of stem cells and their biology is presented in an interesting and well-referenced monograph.

Study Questions

Clinical Focus Question The T and B cells that differentiate from hematopoietic stem cells recognize as self the bodies in which they differentiate. Suppose a woman donates HSCs to a genetically unrelated man whose hematopoietic system was totally destroyed by a combination of radiation and chemotherapy. Suppose further that, although most of the donor HSCs differentiate into hematopoietic cells, some differentiate into cells of the pancreas, liver, and heart. Decide which of the following outcomes is likely and justify your choice.

a. The T cells from the donor HSCs do not attack the pancreatic, heart, and liver cells that arose from donor cells, but mount a GVH response against all of the other host cells.

b. The T cells from the donor HSCs mount a GVH response against all of the host cells.

c. The T cells from the donor HSCs attack the pancreatic, heart, and liver cells that arose from donor cells, but fail to mount a GVH response against all of the other host cells.

d. The T cells from the donor HSCs do not attack the pancreatic, heart, and liver cells that arose from donor cells and fail to mount a GVH response against all of the other host cells.

1. Explain why each of the following statements is false.

a. All Th cells express CD4 and recognize only antigen associated with class II MHC molecules.

b. The pluripotent stem cell is one of the most abundant cell types in the bone marrow.

c. Activation of macrophages increases their expression of class I MHC molecules, making the cells present antigen more effectively.

Go to www.whfreeman.com/immunology : Self-Test

Review and quiz of key terms d. Lymphoid follicles are present only in the spleen and lymph nodes.

e. Infection has no influence on the rate of hematopoiesis.

f. Follicular dendritic cells can process and present antigen to T lymphocytes.

g. All lymphoid cells have antigen-specific receptors on their membrane.

h. All vertebrates generate B lymphocytes in bone marrow.

i. All vertebrates produce B or T lymphocytes and most produce both.

2. For each of the following situations, indicate which type(s) of lymphocyte(s), if any, would be expected to proliferate rapidly in lymph nodes and where in the nodes they would do so.

a. Normal mouse immunized with a soluble protein antigen b. Normal mouse with a viral infection c. Neonatally thymectomized mouse immunized with a protein antigen d. Neonatally thymectomized mouse immunized with the thymus-independent antigen bacterial lipopolysaccha-ride (LPS), which does not require the aid of TH cells to activate B cells

3. List the primary lymphoid organs and summarize their functions in the immune response.

4. List the secondary lymphoid organs and summarize their functions in the immune response.

5. What are the two primary characteristics that distinguish hematopoietic stem cells and progenitor cells?

6. What are the two primary roles of the thymus?

7. What do nude mice and humans with DiGeorge's syndrome have in common?

8. At what age does the thymus reach its maximal size?

a. During the first year of life b. Teenage years (puberty)

c. Between 40 and 50 years of age d. After 70 years of age

9. Preparations enriched in hematopoietic stem cells are useful for research and clinical practice. In Weissman's method for enriching hematopoietic stem cells, why is it necessary to use lethally irradiated mice to demonstrate enrichment?

10. What effect does thymectomy have on a neonatal mouse? On an adult mouse? Explain why these effects differ.

11. What effect would removal of the bursa of Fabricius (bur-sectomy) have on chickens?

12. Some microorganisms (e.g., Neisseria gonorrhoeae, Mycobacterium tuberculosis, and Candida albicans) are classified as intracellular pathogens. Define this term and explain why the immune response to these pathogens differs from that to other pathogens such as Staphylococcus aureus and Streptococcus pneumoniae.

13. Indicate whether each of the following statements about the spleen is true or false. If you think a statement is false, explain why.

a. It filters antigens out of the blood.

b. The marginal zone is rich in T cells, and the periarteriolar lymphoid sheath (PALS) is rich in B cells.

c. It contains germinal centers.

d. It functions to remove old and defective red blood cells.

e. Lymphatic vessels draining the tissue spaces enter the spleen.

f. Lymph node but not spleen function is affected by a knockout of the Ikaros gene

14. For each type of cell indicated (a-p), select the most appropriate description (1-16) listed below. Each description may be used once, more than once, or not at all.

Cell Types a. Common myeloid progenitor cells b. Monocytes c. Eosinophils d. Dendritic cells e. _Natural killer (NK) cells f. Kupffer cells g. Lymphoid dendritic cell h. Mast cells i. Neutrophils j. M cells k. _Bone-marrow stromal cells l. Lymphocytes m__NK1-T cell n. Microglial cell o. Myeloid dendritic cell p. Hematopoietic stem cell

Descriptions

(1) Major cell type presenting antigen to TH cells

(2) Phagocytic cell of the central nervous system

(3) Phagocytic cells important in the body's defense against parasitic organisms

(4) Macrophages found in the liver

(5) Give rise to red blood cells

(6) An antigen-presenting cell derived from monocytes that is not phagocytic

(7) Generally first cells to arrive at site of inflammation

(8) Secrete colony-stimulating factors (CSFs)

(9) Give rise to thymocytes

(10) Circulating blood cells that differentiate into macrophages in the tissues

(11) An antigen-presenting cell that arises from the same precursor as a T cell but not the same as a macrophage

(12) Cells that are important in sampling antigens of the intestinal lumen

(13) Nonphagocytic granulocytic cells that release various pharmacologically active substances

(14) White blood cells that migrate into the tissues and play an important role in the development of allergies

(15) These cells sometimes recognize their targets with the aid of an antigen-specific cell-surface receptor and sometimes by mechanisms that resemble those of natural killer cells.

(16) Members of this category of cells are not found in jaw-less fishes.

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