CELLS, TISSUES and ORGANS of the IMMUNE SYSTEM

CELLS of the immune system

LEUCOCYTES (WBCs) for both specific and non specific immunity. Origination pluripotent stem cells (fetal liver & bone marrow of animal host) Pluripotent- not yet committed to differentiate. PSC can differentiate in to Hematopoietic stem cells (HSCs) which become leucocytes.

Hematopoiesis
HSC (Hematopoietic Stem Cell)
Reside in Bone Marrow Pluripotent 1 HSC Per 50,000 BM Cells (~3x108 cells in Mouse Bone Marrow) Extremely Proliferative If Need Arises

HSC Differentiates to LPC (lymphoid progentor cell) or MSC (myeloid stem cell) Growth Factors and Cytokines Determine Path Once LPC or MSC, Committed Stromal Cells Are Supporting Cells In BM (endothelial, fat cells, fibroblasts, macrophages)

PSC in BM divide to form 2 blood cell lineages: Lymphoid stem cellsB cells (AB secreting plasma cells) T cells activated T cells and NK cells Myeloid stem cells Granulocytes neutrophils, eosinophils, basophils Agranulocytes: Monocytes Macrophages and dendritic cells Mast cells precurssor unknown Megakaryocytes platelets Erythroblast - erythrocytes

Monocytes and Macrophages

Highly phagocytic make up the monocytemacrophage system. Monocytes- mononuclear leucocytes, nucleus ovoid or kidney shaped Granules in cytoplasm stain gray-blue with basic dyes Produced in BM Enter blood circulate for about 8 hours, enlarge , migrate to tissues and mature in to macrophages or dendritic cells

 Macrophages- derived from monocytes, Classified as mononuclear phagocytic leucocytes Larger than monocytes, PM lined with microvilli. Surface molecules- function as receptors to nonspecifically recognise common components of pathogens. Receptors bind LPS, PG. fungal wall- Zymosan, Viral NAs and foreign DNA Receptors for ABs and serum glycoproteins Complement also present. Help in phagocytosis.

Monocyte vs M

M Capturing Bacteria

Granulocytes
Irregular nuclei, 2-5 lobes- polymorphonuclear leucocytes. Cytoplasmic matrix reactive substances that kill MO and enhance inflamation. 3 types: -Basophils -Eosinophils - Neutrophils (Polymorphonuclear neutrophils/PMNs)

Basophils
Irregular nucleus, 2 lobed Granules stain bluish-black with basic dyes Non-phagocytic Release specific cpds from cytoplasmic granules in response to stimulus Eg-histamines, prostaglandins, serotonin Possess high affinity receptors for one type of AB IgE, associated with allergic responses.

BASOPHILS AND MAST CELLS

Have basophilic granules, stain bluish black with basic dyes. which contain allergic mediators. Basophils circulate, mast cells found in tissue.
basophil

degranulating mast cell

Basophilic granules of mast cells

intact mast cell

Eosinophils
Two lobed nucleus Granules stain red with acidic dyes. Migrate from blood stream in to tissue spaces, especially mucous membrane Important in defense against protozoans and helminthes. Damage PM of parasites Eosinophils increase during allergic reactions, especially type I hypersensitivity. Have granules with histaminases and acrylsulphatases,down regulators of inflamatory mediators histamines and leukotrienes respectively.

EOSINOPHILS
Have granules that stain red with eosin Y. Mediate late phase of allergic response, active in immune response to parasites & tumors (antibodydependent cell-mediated cytotoxicity).

eosinophil

PMNs comparison of PMNs to eosinophil

Neutrophils
Stain readily at neutral pH Nucleus 3-5 lobed Contain inconspicuous organelles- primary and secondary granules Granules contain lytic enzymes and bactericidal substances Primary granules- peroxidase, lysozyme, defensins and hydrolytic enzymes Secondary granules- collagenase, lactoferrin, lysozymes etc. Help in intracellular digestion after phagocytisis. Phagocytic Neutrophils circulate in blood. Rapid migration to site of tissue damage and infection

GRANULOCYTES Polymorphonuclear leukocytes (PMNs) Neutrophils: Predominant type of white blood cell. Rapidly migrate to sites of infection or inflammation. Phagocytic, they have special enzymatic pathways for enhanced bacteriocidal action.

Mono

PMN

Comparison of mono to PMN

PMN, note tri-lobed nucleus WrightGiemsa,

 Mast cells: BM derived cells, differentiate in blood and connective tissue. Similar to basophils but cellular lineage different. Mast cells and basophils play important role in development of allergies and hypersensitivities

Dendritic cells
0.2% of WBCs Role in nonspecific resistance Present in skin and mucous membranes of nose, lungs, intestine. Contact pathogens-phagocytose-process antigens and display foreign antigens on surface process is known as ANTIGEN PRESENTATION

Dendritic Cells
Professional APCs Several Types
Langerhans (LC) found in skin Circuilating DCs
Myeloid (MDC1 and MDC2) Plasmacytoid

Interstitial DCs, populate organs such as heart, lungs, liver, intestines Interdigitating DCs, T-cell areas of lymph nodes and Thymic medulla

Dendritic Cells

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Developmental Pathway of DCs

Lymphocytes
Major cells of the immune system 3 types T cells B cells Null cells (Natural killer cells)

Lymphocytes
Major subtypes are T and B lymphocytes (or cells). Responsible for immunological memory. T cells mature in thymus; B cells in avian bursa of Fabricius, mammalian fetal liver & bone marrow. T cells participate in cell-mediated immunity & immunoregulation B cells synthesize antibodies. NK cells are morphologically similar to T & B cells are cytotoxic in absence of priorstimulation.

 Lymphocytes do not actively replicate like other somatic cells. They differentiate and are blocked from exiting the Go phase. Lymphocytes require a specific antigen to bind to a surface receptor. (B and T cell receptors) Cells activate and enter mitosis. Once activated the lymphocytes replicate and circulate making several clones. In addition to activation some cells are inhibited from replicating waiting to be activated by same antigen later- Memory cells

Lymphocytes
Produce antibodies B-cells mature in bone marrow then concentrate in lymph nodes and spleen T-cells mature in thymus B and T cells mature then circulate in the blood and lymph Circulation ensures they come into contact with pathogens and each other

B -Lymphocytes
There are 10 million different B-lymphocytes, each of which make a different antibody. The huge variety is caused by genes coding for abs changing slightly during development. There are a small group of clones of each type of B-lymphocyte

B -Lymphocytes
At the clone stage antibodies do not leave the Bcells. The abs are embedded in the plasma membrane of the cell and are called antibody receptors. When the receptors in the membrane recognise an antigen on the surface of the pathogen the B-cell divides rapidly. The antigens are presented to the B-cells by macrophages

B -Lymphocytes

B -Lymphocytes
Some activated B cells PLASMA CELLS these produce lots of antibodies, < 1000/sec The antibodies travel to the blood, lymph, lining of gut and lungs. The number of plasma cells goes down after a few weeks Antibodies stay in the blood longer but eventually their numbers go down too.

B -Lymphocytes
Some activated B cells MEMORY CELLS. Memory cells divide rapidly as soon as the antigen is reintroduced. There are many more memory cells than there were clone cells. When the pathogen/infection infects again it is destroyed before any symptoms show.

T-Lymphocytes
Mature T-cells have T cell receptors which have a very similar structure to antibodies and are specific to 1 antigen. They are activated when the receptor comes into contact with the Ag with another host cell (e.g. on a macrophage membrane or an invaded body cell)

T-Lymphocytes
After activation the cell divides to form: T-helper cells secrete CYTOKINES help B cells divide stimulate macrophages Cytotoxic T cells (killer T cells) Kill body cells displaying antigen Memory T cells remain in body

Null Cells
Small population of large non-granular lymphocytes, play a role in innate immunity. Do Not Express Classical Lymphocyte Markers Eliminate Tumor Cells and Virally Infected Cells Two modes of recognising targets: Bind to antibody that coat malignant cells thus the antibody bridges the two cell types- Antibody dependent cell-mediated toxicity (ADCC) and result in death of the cell. Presence of special proteins on surface of all host cells called as MHC I antigen. If host cell loses this MHC protein as when some virus or cancer cells overtake the cell, the NK cell kills it by releasing pore-forming proteins and cytotoxic enzymes called granzymes. Together they lyse the target cell.

OVERVIEW OF THE IMMUNE SYSTEM

Cells: lymphocytes, macrophages & monocytes, dendritic cells, granulocytes. All arise from pluripotent hematopoietic stem cells in bone marrow. Organs: lymph nodes (found in various locations), thymus, spleen - these constitute the lymphoid organs Thymus and bursa (bone marrow) are called central lymphoid organs Peripheral Lymphoid Organs: Except lymph nodes, spleen, and tonsils, liver, intestine and skin are also are also important parts of the immune system.

Organs Of Immune System

Primary Lymphoid Organs: where immature lymphocytes mature and differentiate into antigen sensitive B and T cells. Secondary Lymphoid Organs: area where lymphocytes encounter and bind antigen, proliferate and differentiate in to fully active antigen-specific effector cells.
Spleen, lymph nodes, MALT (mucosal associated lymph tissue) GALT (gut associated lymph tissue) and SALT (skin associated lymph tissue) Trap antigen, APC, Lymphocyte Proliferation Bone Marrow (B cells) and Thymus (T cells) Maturation Site

 Primary lymphoid organs and tissues: Immature undifferentiate lymphocytes are generated in BM Mature and are committed to a specific antigen within primary lymphoid organs/tissues.

 Thymus: Highly organised lymphoid organ above the heart Precursor cells from BM migrate into the outer cortex of the thymus and proliferate They mature and acquire T-cell surface markers, and approx 90% die. Selection process in which T cells that recognise host (self) antigens are destroyed. Remaining 10% move in to medulla of thymus, mature into T-cells, and enter in to blood stream.

Thymus
Bilobed Organ on Top of Heart Reaches Max. Size During Puberty
70g infants, 3 g in adults

95-99% Of T Cells Die in Thymus

self reactivity or no reactivity to Ag

Consists of Cortex and Medulla Rat Thymocytes Sensitive to Glucorticoids

 Bone marrow: BM is the site of B cell maturation in mammals. Selective process within BM eliminates B cells with self reactive antigen receptors. In birds undifferentiated lymphocytes move from BM to Bursa of Fabricius where B cells mature.

Thymus

Secondary lymphoid organs and tissues

Spleen: Large organ in abdominal cavity. Filters blood and traps blood borne microbes and Ags. Once trapped by splenic macrophages or dendritic cells, pathogen is phagocytosed, killed and digested Resulting peptide antigens are delivered to macrophages or dendritic cell surface where they are presented to B and T cells.

Lymphatic System
Plasma From Blood Seeps Into Tissue Interstitial Fluid Either Goes Back or Becomes Lymph Lymph Enters Lymphatic Vessels Thoracic Duct Is Largest Lymphatic Vessel Empties Into Left Subclavian Vein Lymphatic Vessel Depends On Muscle Contractions For Movement One Way Valves Ensure One Direction Lymph Nodes Act As Filters For Antigens

Lymphatic System

Lymph Node

Lymph nodes
Lymph nodes lie at junction of lymphatic vessels. They filter harmful microbes and antigens from lymph Pathogens and antigens are trapped by phagocytic macrophages and dendritic cells. Foreign material are phagocytosed and antigens presented to lymphocytes. Within lymph nodes B-cells differentiate into memory cells and antibody secreting plasma cells. Involves specialised T cells called T-helper cells Dendritic cells and macrophages present antigens to Thelper cells that secrete cytokines and promote B-cell immune response.

 Lymphoid tissues are found throughout the body and act as centres for antigen sampling and processing. Lymphoid tissues are found as highly organised or loosely associated cellular complexes. Some lymphoid cells are closely associated with specific tissues such as skin (SALT), mucous membrane (MALT). SALT and MALT are eg. Of highly organised lymphoid tissues. Loosely associated lymphoid tissue eg BALT (bronchii) characterised by lack of cellular partitioning.

Lymph Node
Multiple Afferent Lymphatics Cortex Paracortex
TH, M, DCs Plasma Cells B-cells, Follicular DCs, M, GCs, Primary Follicles

Medulla

Post Capillary Venule

Allow Lymphocyte Migration From Circuilation Into Lymph Node

One Efferent Lymphatic

Rich In Abs and Lymphocytes

Mucous Membranes S.A=400m2 Mucous Membr. Most Common Pathogen Entry Site M.M Protected by MALT Organization Varies (most organized P.P, Tonsils, appendix GI Tract, IEL Unique TCRs Lamina Propia (below epithelium) M, B cells, TH M Cell Allows Ag Entry, Unique Architecture

Mucosal Associated Lymphoid Tissue (MALT)