LECTURE 2- CELLS AND ORGANS OF THE IMMUNE

SYSTEM

Dr. Syeda Saleha Hassan27-8-2014

Molecular Immunology

BIOT 307

Lecture Objectives

After this lecture and the appropriate reading you should know• The process of cell production-haematopoiesis• Some key features of cells involved in the immune

response• How cells circulate in the body• Primary and secondary lymphoid organs

Haematopoeisis

Normal Adult blood cell counts

Cellular Elements of Blood

Uses of adult stem cells to treat disease

Illustration by Cell Imaging Core of the Center for Reproductive Sciences

How does haemotopoiesis work?• Bone marrow stromal cells support the

growth and differentiation of stem cells• Stromal cells include: Fat cells,

endothelial cells, fibroblasts and macrophages

• Provide a supporting matrix for cell growth (cell to cell contact)

• Provide soluble growth factors for cell differentiation e.g. erythropoietin

How is haemotopoiesis controlled?• Expression of certain genes control

development of certain cell types• Removal of some cells by induction of

programmed cell death-apoptosis

Functions and characteristics of cells of the immune system

• Mainly found in tissues • Release of granules containing

histamine and other compounds• Important in inflammation and

allergy

• Smallest WBC in circulation• Function unknown• Maybe similar to mast cells

• Attack and killing of large antibody coated parasites such as worms

All these cells are degranulating cells

Functions and characteristics of cells of the immune system

• Only enter tissues when instructed• Phagocytosis• Bactericidal killing mechanisms e.g.

respiratoy burst

• Resident in tissues• Phagocytosis• Bactericidal killing mechanisms e.g.

nitric oxide production• Antigen processing and presentation

• Antigen recognition/uptake• Antigen presentation-produce cytokines

to direct T cell response e.g. IL-12

Functions and characteristics of cells of the immune system

• Important in innate immune response recognises foreign/infected cells

• Destroys them by release of toxic granules

• Releases cytokines e.g. Interferon gamma (IFN-γ)

• CD4 T cells:

Important in specific immune response produce cytokines to activate macrophages and B cells and to regulate the immune response

• CD8 T cells:

Important in specific immune response recognise and kill infected cells in a specific manner.• Produce cytokines

Functions and characteristics of cells of the immune system

• Important in adaptive immune response

• Synthesise and secrete antibodies (Immunoglobulin Ig)

Identification of cell types- CD molecules

Organs of the immune systemPrimary:• Thymus• Bone Marrow

Secondary:• Spleen• Lymph nodes• Mucosal

Associated Lymphoid Tissue

BloodLymphatics

Bone Marrow-site of lymphocyte production and B cell maturation

• T cells produced in bone marrow migrate to thymus to develop in humans and mice B cells originate and develop in bone marrow

• Interactions with cell adhesion molecules on stromal cells promote B cell growth production of IL-7 promotes maturation

x40 magnification of bone marrow

Thymus-site of T cell maturation• Cortex-densely

packed with immature T cells (thymocytes)

• Medulla-fewer thymocytes

• Stromal cell network interaction with developing thymocytes

• Production of thymic hormones• Expression of MHC molecules

important in positive and negative selection of T cells

Thymus declines with age

Absence of thymus results in no T cell development-severe immunodeficiency

Mouse- Nude Mouse

Humans-DiGeorge’s syndrome

Thymus details• Derived from the third and fourth pharyngeal pouches during the

embryonic life and attracts (by chemoattractive molecules) circulating T- cell precursors derived from HSC in the bone marrow.

• Site of T-cell development and maturation.• Flat, bilobed organ situated behind the sternum, above and in front of

the heart.• Each lobe surrounded by a capsule and divided into lobules, which

are separated from each other by strands of connective tissue called trabeculae.

• Each lobule is organized into two compartments.

1. Cortex: The outer compartment, is densely packed with immature T cells, called thymocytes.

2. Medulla: The inner compartment, is sparsely populated with thymocytes.

Thymus• Both the cortex and the medulla are criss-crossed by a three

dimensional stromal cell network composed of epithelial cells, dentritic cells, and macrophages, which make up the framework of the organ and contribute to the growth and maturation of the thymocytes.

• The accessory cells are important in the differentiation of the immigrating T cell precursors and their education (positive and negative selection), prior to their migration into the secondary lymphoid tissues.

• Thymic epithelial cells produces the hormones thymosin and thymopoietin and in concert with cytokines such as IL-7 are probably important for the development and maturation of thymocytes into mature cells.

• The thymic cortex is the major site of activity and thymocyte proliferation, with a complete turnover of cells approximately every 72 hours.

Thymus• These thymocytes then move into the medulla, where they undergo

further differentiation and selection and finally migrate via circulation to the secondary lymphoid organs/ tissues where they are able to respond to microbial antigens.

• Most (95%) of the thymocytes generated each day in the thymus die by apoptosis with less than 5% surrviving.

• Molecules important to T cell function such as CD4, CD8 and T cell receptor develop at different stages during the differentiation process.

• The main functions of the thymus as a primary lymphoid organ are:1. To produce sufficient numbers (millions) of different T cells

each expressing unique T cell receptors such that, within this group, there are at least some cells potentially specific for huge number of microbial antigens in our environment (generation of diversity).

2. To select for survival those T cells which bind weakly to self MHC molecules (positive selection), but then to eliminate those which bind too strongly to these same self MHC molecules (negative selection) so that the chance for an autoimmune response is minimized.

Lymph nodes-site where the immune response is mounted

Very important structures first organised structures to see antigen delivered from the tissues via the lymphatic system

Lymphatic system

The three layers of a lymph node support distinct microenvironments.

Lymphatic system • The left side depicts the arrangement of reticulum and lymphocytes within the various regions of a lymph node. Macrophages and dendritic cells, which trap antigen, are present in the cortex and paracortex. THcells are concentrated in the paracortex; B cells are primarily in the cortex, within follicles and germinal centers. The medulla is populated largely by antibody-producing plasma cells. Lymphocytes circulating in the lymph are carried into the node by afferent lymphatic vessels, they either enter the reticular matrix of the node or pass through it and leave by the efferent lymphatic vessel.

• The right side depicts the lymphatic artery and vein and the postcapillary venules. Lymphocytes in the circulation can pass into the node from the postcapillary venules by a process called extravasation (inset)

Spleen-site where an immune response is mounted

B cells

Macrophages and T cells

T cells

• The spleen, which is about 5 inches long in the adult, is the largest lymphoid organ. It is specialized for trapping blood-borne antigens.

• Diagrammatic cross section of the spleen. The splenic artery pierces the capsule and divides into progressively smaller arterioles, ending in vascular sinusoides that drain back into the splenic vein. The erythrocyte-filled red pulp surrounds the sinusoids. The white pulp forms a sleeve, the periarteriolar lymphoid sheath (PALS), around the arterioles; this sheath contains numerous T cells. Closely associated with PALS is the marginal zone, an area rich in B cells that contains lymphoid follicles that can develop into secondary follicles containing germinal centers.

Spleen ultrastructure

Spleen Human spleen (stained for B cells)

RP=red pulp

MZ=marginal zone

GC=germinal centre

PALS=periarteriolar lymphoid sheath

Mucosal Associated Lymphoid TissueCross-sectional diagram of the mucous membrane ling the intestine, showing a Peyer’s patch lymphoid nodule in the submucosa. The intestinal lamina contains loose clusters of lymphoid cells and diffuse follicles.

Gut associated lymphoid tissue (GALT)

e.g. tonsils, appendix

Peyers Patch under the epithelial layer of the intestine

Loose clusters of B cells, plasma cells, T cells and macrophages

Mucosal Associated Lymphoid Tissue

Antigen transported across the epithelial layer by M cells at an inductive site activates B cells in the underlying lymphoid follicles. The activated B cells differentiate into IgA-producing plasma cells, which migrate along the submucosa. The outer mucosal epithelial layer contains intraepithelial lymphocytes, of which are T cells.