CELLS, TISSUES and ORGANS of the IMMUNE SYSTEM

CELLS of the immune system

• LEUCOCYTES (WBC’s)– 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 (HSC’s) 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 cells-• B 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 monocyte-macrophage system.

• Monocytes- mononuclear leucocytes, nucleus – ovoid or kidney shapedGranules in cytoplasm stain gray-blue with basic dyesProduced in BMEnter 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 leucocytesLarger 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 NA’s

and foreign DNAReceptors for AB’s 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

intactmast cell

Basophilic granules of mast cells

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 (antibody-dependent cell-mediated cytotoxicity).

PMNs

eosinophil

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.

PMN, note tri-lobed nucleus Wright-Giemsa,

Mono PMN

Comparison of mono to PMN

• 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 WBC’s• 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

• 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

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 B-cells.• 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 CELLSthese 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

• 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.

Null Cells

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.– Bone Marrow (B cells) and Thymus (T cells)– Maturation Site

• 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

• 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.

• 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

Thymus

• 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.

• 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

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 T-helper

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.

• Multiple Afferent Lymphatics• Cortex

– B-cells, Follicular DCs, M, GCs, Primary Follicles• Paracortex

– TH, M, DCs• Medulla

– Plasma Cells• Post Capillary Venule

– Allow Lymphocyte Migration From Circuilation Into Lymph Node• One Efferent Lymphatic

– Rich In Abs and Lymphocytes

Lymph Node

• 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)