1. Immune system, lymphoid organs
for pharmacists
by Krisztina H.-Minkó Semmelweis University Department of Anatomy, Histology and Embryology 2017
Lymphoid organs, thymus, spleen, lymph nodes, antigen presenting cells, antigene, antibody, bone marrow, tonsils, MALT, SALT

2. The immune system is a network of cells, tissues, and organs that work together to protect the body from infection. The human body provides an ideal environment for many microbes, such as viruses, bacteria, fungi, and parasites, and the immune system prevents and limits their entry and growth to maintain optimal health.
  The immune system recognizes and responds to antigens. Antigens are substances (usually proteins) on the surface of cells, viruses, fungi, or bacteria. Nonliving substances such as toxins, chemicals, drugs, and foreign particles can also be antigens. The immune system recognizes and destroys substances that contain antigens.
CANCER!

3. INNATE IMMUNITY
Innate, or nonspecific, immunity is the defense system with which you were born. It protects you against all antigens. Innate immunity involves barriers that keep harmful materials from entering your body. These barriers form the first line of defense in the immune response. Examples of innate immunity include:
Cough reflex
Enzymes in tears and skin oils
Mucus, which traps bacteria and small particles
Skin
Stomach acid
Innate immunity also comes in a protein chemical form, called innate humoral immunity. Examples include the body's complement system and substances called interferon and interleukin-1 (which causes fever).
If an antigen gets past these barriers, it is attacked and destroyed by other parts of the immune system.
ACQUIRED IMMUNITY
Acquired immunity is immunity that develops with exposure to various antigens. Your immune system builds a defense against that specific antigen.

4. Immune cells

6. Lymphocytes B cell: T cell:
A type of white blood cell and, specifically, a type of lymphocyte.
Many B cells mature into what are called plasma cells that produce antibodies (proteins) necessary to fight off infections while other B cells mature into memory B cells..
All of the plasma cells descended from a single B cell produce the same antibody which is directed against the antigen that stimulated it to mature. The same principle holds with memory B cells. Thus, all of the plasma cells and memory cells "remember" the stimulus that led to their formation.
The maturation of B cells takes place in birds in an organ called the bursa of Fabricus. B cells in mammals mature largely in the bone marrow.
The B cell, or B lymphocyte, is thus an immunologically important cell. It is not thymus-dependent, has a short lifespan, and is responsible for the production of immunoglobulins. It expresses immunoglobulins on its surface.
T cell: 
A type of white blood cell that is of key importance to the immune system and is at the core of adaptive immunity, the system that tailors the body's immune response to specific pathogens. The T cells are like soldiers who search out and destroy the targeted invaders.
TCR on the surface.
Immature T cells (termed T-stem cells) migrate to the thymus gland in the medistinum, where they mature and differentiate into various types of mature T cells and become active in the immune system in response to a hormone called thymosin and other factors. T-cells that are potentially activated against the body's own tissues are normally killed or changed ("down-regulated") during this maturational process.
There are several different types of mature T cells. Not all of their functions are known. T cells can produce substances called cytokines such as the interleukins which further stimulate the immune response (T helper cells, CD4+ cells).
Citotoxic T cells (TC cells, or CTLs) destroy virus-infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8+T cells since they express the CD8 glycoprotein at their surfaces. 

7. B cell: immunoglobulin production, humoral immune response
T cell: TCR receptor, cellular immunity

9. B cell
(soluble antigenes)

11. MHC-molecules Idős néni 1 db almával a piacon, APC maga a piac
Yoram Reiter Laboratory
Department of Biology Technion - Israel Institute of Technology, Haifa 32000, Israel.
Projects:  TCR-peptide-MHC interaction

12. T cells: juxtacrin communication
T cell receptor

13. T lymphocyte functions
T helper
T citotoxic
Connexions; Adaptive Immune Response; Figure 4: Naïve CD4+ T cells engage MHC II molecules on antigen-presenting cells (APCs) and become activated. Clones of the activated helper T cell, in turn, activate B cells and CD8+ T cells, which become cytotoxic T cells. Cytotoxic T cells kill infected cells.

14. Antigen presenting cells (APC), Dendritic cells
MBBS Medicine (Humanity First) / Antigen presenting cells of the skin called dendritic cells

16. Localisation of lymphocytes in the body

17. The lymphatic system
Primary lymphatic organs are where lymphocytes are formed and mature. They provide an environment for stem cells to divide and mature into B- and T- cells:
Both T-cell and B-cells are 'born' in the bone marrow.
However, whereas B cells also mature in the bone marrow, T-cells have to migrate to the thymus, which is where they mature in the thymus.
Multiplication is not dependent on the presence of antigens.
Secondary lymphoid tissues are arranged as a series of filters monitoring the contents of the extracellular fluids, i.e. lymph, tissue fluid and blood. The lymphoid tissue filtering each of these fluids is arranged in different ways. Secondary lymphoid tissues are also where lymphocytes are activated.
These include: lymph nodes, tonsils, spleen, Peyer's patches and mucosa associated lymphoid tissue (MALT).
Multiplication is dependent on the presence of antigens.
cancer-help/about-
cancer/what-is-cancer/
body/the-lymphatic-system

18. LYMPHOID TISSUE
is connective tissue characterized by a rich supply of lymphocytes.
Free within the regular connective tissue or is surrounded by capsules, forming the
lymphoid organs.
Dark blue in HE
Rich network of reticular fibers (III. coll) , reticular cells
Exception: IN THYMUS : reticulum of unusual epithelial cells
Free lymphoid tissue or „encapsulated”
Lymphoid infiltration
Macrophages, plasma cells

19. Primary lymphoid organs (human)

20. Bone marrow (medulla ossium rubra)

21. Bone marrow (medulla ossium)
Stromal cells
B and T cell precursors

22. T for thymus

23. THYMUS Bilateral organ Mediastinum T cell maturation
Unique structure: epithelium from the
3rd pharyngeal pouches invaded
by lymphoblasts

24. THYMUS HISTOLOGY
CT capsule, trabeculae, incomplete lobules, cortex stains more darkly

26. Thymic cells, cortex, medulla

27. Cytoreticulum
(euchromatic epithelial nuclei)
desmosomes
Blood-thymus barrier in the cortex
Hassall’s corpuscules:
keratin, calcification
Function?
Only efferent lymphatics

28. Thymus lymphaticus

29. Thymus, cortex, medulla, Hassall’s body

30. Development: from the caudal part of the 3rd pharyngeal pouch

32. „aged” Thymus adiposus

33. Secondary lymphoid organs (human)

34. LYMPH NODE/ nodus lymphaticus
Bean-shaped, encapsulated structures (2-10 mm)
Distributed throught the body along the course of lymphatic vessels
In-life filters that are important in the body’s defence against
microorganisms and the spread of tumor cells
Lymp (tissue fluid) is filtered by at least one node before
returning to the circulation

35. Convex surface: entrance for lymph: afferent lymph vessels
PARTS of the lymph
node:
CORTEX
PARACORTEX
MEDULLA
Convex surface: entrance for lymph: afferent lymph vessels
Concave depression: hilum (efferent lymph vessels, arteries, nerves, veins)
Connective tissue capsule, trabeculae
Reticular connective tissue

36. folliculus lymphaticus/lymphoid nodules/lymph follicle
Unit of the lymphatic tissue
primary without germinal center (intrauterin or germ free conditions)
secondary follicule (with germinal center). .

37. folliculus lymphaticus
Found in secondary lymphatic organs, or as solitaer lymph follicles (usually under epithelia)
In tonsils and mucosa
Spherical structures (100 mm. to 1 mm)
Contains mainly B cells
Site of B lymphocyte activation by antigen bearing macrophage or follicular dendritic cells (FDC)
Germinal center (centrum germinativum): site of B lymphocyte proliferation, pale staining
Marginal zone
LOCATION:
Free
Lymph nodes
Spleen
Tonsils
NOT in THYMUS!!!!

38. IN THE CORTEX:
reticular cells,
macrophages,
APCs (dendritic cells, B ly, MHC II
on the surface)
lymphocytes
lymphoid nodules (follicules)
interfollicular areas
subcapsular sinuses
cortical sinuses
IN THE PARACORTEX (DEEP CORTEX):
NO NODULES (no B cells, but T cells mainly)
interdigitating dendritic cells
and T cells
in venules lymphocytes enter
across the vessel wall (HEV)
IN THE MEDULLA:
medullary cords (B cells, plasma cells, macrophages)
medullary sinuses (dilated space between the cords, frequently bridged by reticular cells and fibers)

39. Lymph flow:
aff. lymph vessels, subcapsular sinuses, cortical sinuses, intermediate or trabecular sinuses,
medullary sinuses, terminal sinuses.
During the passage the lymph is filtered and modified by the immune cells.
Finally lymph is collected by the efferent lymphatics.

40. Lymph node

41. THE MECHANISM OF LYMPH FORMATION
From arterial end of capillaries fluid
is filtered into the extracellular space
Fluid gets back to the venous end
of capillaries and through lymphatics

42. HISTOLOGY OF LYMPH VESSELS
lymphatic capillary
valve
nucleus of
endothelial cell

43. SPLEEN/LIEN

44. Largest single accumulation of lymphoid tissue
Involved in filtration of blood (defense against blood-borne antigens)
Destruction site of erythrocytes
Production site of antibodies and activated lymphocytes
Any inert particles in blood are actively phagocytosed by spleen macrophages

45. Spleen structure
Capsule (dense CT), trabeculae (subdivide parenchyma, splenic pulp)
Hilum (trabeculae: arteries, veins, lymphatics)

46. Splenic pulp
Reticular tissue (reticular cell, lymphocytes, blood cells, macrophages, APCs
2 components:
WHITE PULP: lymphoid nodules and periarteriolar lymphoid sheathes
„PURPLE STAINING”
RED PULP: blood-filled sinusoids and splenic cords (of Bilroth)
„REDDISH STAINING”

48. CIRCULATION IN THE SPLEEN
Splenic artery, trabecular arteries, central arterioles (surrounded by PALS, periarteriolar lymphatic sheath),
PALS receive large number of lymphocytes (B cells) and may form lymphoid nodules, a. is eccentric but still
called central arteriole, smaller branch supply the lymphoid tissue
MAGINAL ZONE: surrounding nodules (blood sinuses, lymphoid tissue: lymphocytes, macrophages
In the red pulp: penicillar arterioles, splenic cords (network of reticular cells and fibers, lymphocytes,
macrophages, plasma cells, erythrocytes, platelets, granulocytes)
and venous sinusoids (lined by stave cells, oriented in parallel with the sinusid’s blood flow, sparsely
wrapped in reticular fibers set in a transverse direction, like hoops surrounding the staves of a wooden keg)

49. WHITE PULP:
Central arteriole
PALS (T cells)
Splenic nodules (Malpighian nodules, B cells, a. is eccentric)
Marginal zone (loose lymphoid tissue, B cells, marginal sinuses, macrophages).

50. Spleen: white pulp

51. RED PULP
Splenic cords and sinuses
network of reticular cells and
fibers, lymphocytes,
macrophages, plasma cells,
erythrocytes, platelets,
granulocytes

52. Blood flow in the red pulp
Closed circulation:
Penicillar arterioles or
Capillaries branching from them connects directly to the sinusoids
Open circulation:
Other penicillar arterioles are open-ended dumping blood into the stroma of the splenic cords
Red pulp veins, trabecular veins, splenic vein

53. Immunohistochemistry
T and B dependent regions in the
human spleen
CD3 positive T cells
CD20 positive B cells

54. T and B dependent areas in different lymphoid organs

55. MALT mucosa-associated lymphoid tissue:
free lymphocytes and follicles in various sites in the body where antigens are present
(gut, lungs, salivary glands etc.)
No capsule
In some places aggregates form
(tonsils, Peyer’s patches, appendix)
70% of the immun cells are in the MALT!

56. Tonsils In the mucosa, local immunological protection
Waldeyer’s lymphatic ring: pharynx, palate, auditory tube, root of the tongue
Epithelial covering depends on the location and lymphoreticular tissue, no sinuses

57. General structure of the tonsils
Follicles
Interfollicular area
Tonsillar crypts
Lymphoid infiltration with macrophages
Reticular epithelium
Discontinous lamina basalis

58. Tonsilla palatina Epithelium: stratified squamous non keratinized
Crypts are deep
Lymphoid infiltration in the epithelium
hemi-capsule!!!
HEV (high endothelial venules)

59. Tonsilla palatina

60. Tonsilla palatina

61. Lymphoid infiltration in the epithelium of the crypt

62. HEV: high endothelial venule

63. HEV and normal „venule”

64. Tonsilla lingualis Behind terminal sulcus, pars follicularis
No papillae here
Epithelium:
stratified squamous non keratinized
Lymphoid infiltration in the epithelium
lamina propria
Striated m., , mucinous acini for cleaning the cryts
Follicles
Crypts are NOT DEEP!
Fossules
NO CAPSULE!!!

65. Tonsilla pharyngea Impaired
Pseudostratified ciliated epithelium with goblet cells
Lymphoid infiltration in the epithelium
Fissures
Crypts are deep
Follicules and interfollicular area
Thin capsule and septae
Sero-mucous acini in proximity

66. Peyer’s patches

67. Thank you for attention!

68. References: „Szövettan” edited by Röhlich Pál (SE)
Molecular cell biology, Lodish et al.
Molecular biology of the cell, Alberts et al.
Co-authors of the lecture: Nóra Fejszák, Katalin Kocsis, Attila Magyar, Nándor Nagy