Lecture 11Immune (Lymphatic) System

I. Overview/definitionsDefinition: Immune (Lymphatic) System -- The immune or lymphatic system consists of acomplex network of specialized cells and organs designed to protect and defend the bodyagainst attacks by "foreign" invaders such as bacteria and viruses.

*The cells of this system are known asimmunocompetent cells in that they have the capacityto distinguish self from altered self or foreign.

*The system has innate components that act rapidly(within hours), but nonspecifically (Innate Immunity- which involves neutrophils and macrophages) andadaptive components that act specifically, but needtime to respond (Acquired or Adaptive Immunity -mediated by lymphocytes, initially takes 4-7 days).

Note: While the terms immune systemand lymphatic system are often usedinterchangeably, technically the lymphaticsystem consists of a series of vascular-likechannels (called Lymphatics) thatdrain off excess tissue fluid, returning it tothe cardiovascular system via the thoracicduct). The lymph fluid within thesechannels drains through regional lymphnodes that serve to filter the lymph fluidon its way to the vascular system.

*The immune system not only protects against extrinsic pathogensbut also against intrinsic pathological changes in cells and tissuesthat result in alterations of cell surface molecules (cancer).

II. Immune System Components: The immune system consists ofspecific cells (lymphocytes, macrophages, etc.), lymphatic organs(thymus, spleen, tonsils, lymph nodes) and diffuse lymphatic tissue -collections of lymphocytes and other immune cells dispersed in thelining of the digestive and respiratory tracts and in the skin.

1. Cells of the Immune System: originate from precursor cellsin the bone marrow and patrol tissues by circulating in either theblood or lymphatics, migrating into connective tissue or collecting inimmune organs.

a. Lymphocytes one of the most important cells of an immuneresponse; responsible for adaptive immunity; 2 major types:

1) B cells-differentiate in the bone marrow of mammals (orthe cloacal bursa of birds), give rise to plasma cells that secreteantibodies into the extracellular fluid, which bind to antigens. Thisantibody/antigen complex is more easily recognized byphagocytes.

2) T Cells-differentiate in the thymus, 70-80% of blood lymphocytes; 3 subtypes:

T helper cells (CD4+)-act through secretion of soluble short-range effector molecules, called cytokines that will stimulate B cells and macrophages

T cytotoxic cells (CD8+)-attach directly to target cells to kill them

Natural Killer Cells-lacks antigen specific receptors that are typical of B and T cells, play an important role in innate immunity; mechanism similar to T cytotoxic cells, important in elimination of tumors and virus-infected cells

Resting Neutrophilsare round with no fibers

Activated Neutrophilsare flat & form fibers

b. Phagocytes - provide innate cellular immunity in tissues and initiate host-defenseresponses (they provide the first line of defense against microorganisms). Three types:

1) Neutrophils (PMNs)--most numerous of the whiteblood cells in dogs & cats, multilobed nucleus, rapidturnover, work well under ischemic conditions,important in the phagocytosis of pathogens

Neutrophils generate extracellularFibers called NETS that kill bacteriaWithout the need for phagocytosis.

NETS

NETS=neutrophilextracellular traps

Neutrophil Extracellular Traps: E. High resolution SEM analysis of NETS that consist of smooth fibers and globular domains. F. TEM analysis of nets.

Gram positive and Gram Negativebacteria associate with neutrophil fibers-NETs appear to be a form ofinnate response that binds micro-organisms, preventing them from spreading and have bactericidal activity

S. FlexneriS. Typhimurium

S. Aureus

c. Other cells 1) Mast Cellsthis resident connectivetissue cell is considered a component of theimmune system. It is found near blood vesselsand contains lots of basophilic granules, thecells release histamine, and slow reactingsubstance of anaphylaxis-->increases vascularpermeability-->edema

b. Phagocytes - provide innate cellular immunity in tissues and initiate host-defense responses(they provide the first line of defense against microorganisms). Three types:

1) Neutrophils (PMNs

2) Macrophages--derived from monocytes that enter the tissue from the blood,phagocytose bacteria and tissue debris; release systemic cytokines that body temp.

Macrophage

Dendritic cell

Neutrophil

Cell Type3) Dendritic Cellscells derived from thebone marrow which are found predominatelyin T-cell areas of lymphoid tissue as well as inthe skin. They are phagocytic when they areimmature and they take up pathogens. Whenmature they have the capacity to bind antigenson their surface and are able to present theseantigens to and are effective in activatingresting T-cells & initiating adaptiveimmune responses.

Mast Cell

2. Organs/tissues of the Immune System: Specialized organs andcollections of tissue where lymphocytes interact with non-lymphoid cells,which are important either to their maturation or to the initiation ofadaptive immune responses. Lymphatic (Immune) tissues arecharacterized by having numerous lymphocytes and significant numbersof reticular fibers. They are classified as follows:

a. Primary (Central) Immune Organs--where stem cells develop anddifferentiate into mature B-cells and T-cells:

1) Bone MarrowB-cells mature in the bone marrow (cloacal bursa in birds)2) Thymusa large organ in the cranial chest in which T-cells mature

b. Secondary (Peripheral) Immune Organsthese organs trap cells orpathogens arriving from sites of infection and antigen is presented to lymphocytesto stimulate adaptive immune responses.

1) Lymph Nodesituated along the extensive drainage system oflymph vessels, they serve to filter the lymph fluid before returning it to the bloodstream(B cells found in follicles, T-cells located in paracortical areas). Lymph nodes providean environment in which lymphocytes are able to respond to lymph-borne antigens.

2) Spleenserves as a filter for the blood, it is involved in clearanceand mounting of immune responses against blood-borne antigens

3) Immune tissue associated with various organs:

GALTgut-associated lymphatic tissue; comprised of lymphoid tissue (lymph nodules) in the intestinal wall containing lymphocytes, plasma cells and macrophages.

MALTmucosa-associated lymphatic tissue; lymphoidtissue associated with the mucosa of the female reproductivetract, respiratory tract, etc.SALTskin-associated lymphatic tissue; lymphatic tissueassociated with the dermis of the skin.

III. Primary Lymphatic Organs:

1. Bone marrow The structure and major hematopoieticfunctions of the bone marrow were covered last semester. Itis the second largest organ in aggregate and is the site ofB cell development and maturation.

BoneMarrowRed Cell Nest

White Cell Nest

2. Thymusa. Function/origin: circulating stem cells migrate to the thymus anddifferentiate into T-lymphcytes; cells undergo a process of maturation andeducation prior to release into the circulation. Embryologically the thymusoriginates as an epithelial outgrowth of the third pharyngeal pouch. Theseepithelial cells of the pouch form the epithelial reticular cells of the thymicstroma.b. Structure: The thymus is covered by an irregular connective tissue capsuleand is divided into lobes that are further separated by thin connective tissuesepta into lobules. The central medulla (core) of each lobule is surrounded byan outer cortex.

Capsule

septa

Histologically:1) Cortex-consists mainly of star shaped cells called epithelial reticular cells withlymphocytes found between the processes of these cells. Because it is loaded with lymphocytes itstains darkly compared to the medulla (see fig. below). Epithelial reticular cells are connected bydesmosomes maintain the structural integrity of the organ and help form the blood-thymus barrier.2) Medulla-has fewer lymphocytes and thus stains lightly. Some epithelial reticular cells in themedulla are larger and form thymic (Hassalls) corpuscles. These are comprised of one orseveral central calcified or degenerated epithelial reticular cells, surrounded by flat keratinizedcells in a concentric arrangement.

Clinical correlation: In certain canine breeds(e.g. Weimaraners) insufficient levels of growthhormone cause the thymus gland to developimproperly. T- lymphocytes that originate in thethymus mature abnormally, and are not aseffective against viruses, protozoa, and fungi.Thus these dogs are subject to recurrentinfections. Condition is greatly improved withgrowth hormone replacement.

Epithelial Reticular Cells: There are 6 types (Type I-VI); types I-III arefound in the cortex and derived from the ectoderm; types IV-VI are found in the medulla and are derived from the endoderm of the 3rdpharyngeal pouch. Type VI cells form thymic corpuscles that are thought to be the site of T lymphocyte death in the medulla.

Important points concerning the thymus:-Lacks afferent lymphatics-Lacks lymph nodules.-blood-thymus barrier exists (type I cells)

IV. Secondary Lymphatic Organs: Lymphocytes leave the primary lymphatic organsand seed the secondary lymphatic organs where they first encounter foreign antigens.Most secondary lymphatic organs are comprised of lymphatic follicles or nodules(consisting of a stromal network of dendritic cells, reticular cells, reticular fibers andtightly packed B-lymphocytes) and diffuse extranodular lymphatic tissue (adjacent tothe nodules; contains dense accumulations of small T-cells, macrophages and somelymphoblasts).

Lymphatic Follicle Peyers PatchLymphatic Follicle (Nodule) - Tonsil

Corona

1. Immune tissue associated with various organsa. Gut-Associated Lymphatic Tissue (GALT): solitary and aggregated lymphatic

nodules associated with the gut including (Peyer's patches, mesenteric lymph nodes and theappendix). It is especially rich in B-cells and is responsible for localized immunity to pathogenssuch as bacteria, viruses, and parasites. The most prominent aggregate of lymphatic nodules of theGALT is located in the ileum and is called Peyers Patches, (seen grossly as elevations of themucosa) present a strong line of defense against invading bacteria, viruses, and other foreignparticles that get into the lumen of the GI tract.Note: The epithelial regions adjacent to the follicles are lined by squamous-like cells,known as M cells (microfold cells) which capture antigens to underlying macrophages.

IleumLumen

Figure 4: Scanning Electron Micrograph of Peyers Patches in thebovine GI tract.

Clinical Note: Johnes Disease in Cattle: When calves ingest M. paratuberculosis, itinvades the last part of the small intestine and is taken up by M cells associated withPeyers Patches. Unfortunately for calves, after the M cells bring M. paratuberculosis tothe Peyer's patch and they are engulfed by macrophages, the bacterium finds itself in anideal location. Macrophages are efficient microbial killers in most cases. For reasons thatare only partially understood, macrophages fail to kill this kind of bacteria. So the bacteriareplicate, ultimately causing inflammation that impairs intestinal function and causesdiarrhea. The ileum becomes thickened by granulomatous inflammation, and a conditionknown as a protein-losing enteropathy occurs (i.e. protein absorption is impaired andexcess protein is lost in the feces). This can ultimately lead to death of the infected animal.

b. Mucosa-Associated Lymphatic Tissue (MALT): solitary lymphatic nodules oraggregates of nodules commonly found in the subepithelial connective tissue of mucousmembranes associated with the female reproductive tract, respiratory tract, and urinarytract. 1) Aggregated lymphatic nodules of the MALT are prominent in the pharyngeal regionwhere they are referred to as tonsils. They are located adjacent to the lumen of the hostorgan and are covered by stratified squamous (oropharynx, see below) orpseudostratified columnar (nasopharynx) epithelium.

Nasopharyngeal Tonsil

Crypt

Nodule

Secondary lymph tissue associated with othertissues/organs

b. Mucosa associated (MALT) Antigens penetrate mucosa and expose lymphatic tissue

NasopharyngealTonsil

Lymphocytes invadeoverlying epithelium

2) The epithelium overlying the tonsils is usually infiltrated to a variable degreewith lymphocytes, neutrophils and macrophages

Clinical Correlation Abnormalities

Immune Deficiences-Immune deficiency diseases sire a groupof disorders in which normal host defenses against disease areimpaired. These include defects in non-specific host defenses(e.g., complement deficiency; functional white blood celldisorders), and defects in specific host defenses (e.g.,immunosuppression caused by pathogenic bacteria, viruses andparasites; combined immune deficiency; IgA deficiency; growthhormone deficiency). Example: Feline Leukemia Virus- a retrovirus,is the most important infectious disease agent producing fatalillness in domestic cats today.

Cancer- the cancer itself can be profoundly immunosuppressive.The form of immunosuppression usually varies with the tumortype. For example, lymphoid tumors (lymphomas and leukemia)tend to suppress antibody formation, whereas tumors of T-cellorigin generally suppress cell-mediated immunity

Immune System 1: Lab Introduction

Bone Marrow: Decalcified hyoid bone from a cow

Periosteum

Cortical Bone

SpongyBone

BoneSpicule

Fat Cells

Bone Marrow

Bone Marrow with Granulocytic and Erythroid Cell Nests

BoneSpicules

Marrow withCell Nests

Higher Magnification: Bone Marrow

Fat Cell

GranulocyticCell Nests

ErythroidCell Nests

Megakaryocyte

Bone Marrow: Granulocytic and Erythroid Cell Nests

Granulocytic cell nestErythroid Cell Nest

Developing White (Granulocytic) Cell Nest

Granulocytic Cells

Medulla

Cortex

capsule

Thymus

Thymus: MedullaEpithelial Reticular Cells

GALT [Ileum]

Lumen

LymphaticNodules

Nasopharyngeal Tonsil showingMucosal invasion by lymphocytes

GerminalCenter

Lymphnodule

Mantle

OropharyngealTonsil

Nasopharyngeal Tonsil