Lecture 11

Immune (Lymphatic) System

I.

Overview/definitions
Definition: Immune (Lymphatic) System -- The immune or lymphatic system consists of a
complex network of specialized cells and organs designed to protect and defend the body
against attacks by "foreign" invaders such as bacteria and viruses.

*The cells of this system are known as

immunocompetent cells in that they have the capacity
to 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) and
adaptive components that act specifically, but need
time to respond (Acquired or Adaptive Immunity mediated by lymphocytes, initially takes 4-7 days).

*The immune system not only protects against extrinsic pathogens

but also against intrinsic pathological changes in cells and tissues
that result in alterations of cell surface molecules (cancer).
Note: While the terms immune system
and lymphatic system are often used
interchangeably, technically the lymphatic
system consists of a series of vascular-like
channels (called Lymphatics) that
drain off excess tissue fluid, returning it to
the cardiovascular system via the thoracic
duct). The lymph fluid within these
channels drains through regional lymph
nodes that serve to filter the lymph fluid
on its way to the vascular system.

II. Immune System Components: The immune system consists of

specific cells (lymphocytes, macrophages, etc.), lymphatic organs
(thymus, spleen, tonsils, lymph nodes) and diffuse lymphatic tissue collections of lymphocytes and other immune cells dispersed in the
lining of the digestive and respiratory tracts and in the skin.
1. Cells of the Immune System: originate from precursor cells
in the bone marrow and patrol tissues by circulating in either the
blood or lymphatics, migrating into connective tissue or collecting in
immune organs.

a.

Lymphocytes one of the most important cells of an immune

response; responsible for adaptive immunity; 2 major types:
1) B cells-differentiate in the bone marrow of mammals (or
the cloacal bursa of birds), give rise to plasma cells that secrete
antibodies into the extracellular fluid, which bind to antigens. This
antibody/antigen complex is more easily recognized by
phagocytes.
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

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)--most numerous of the white
blood cells in dogs & cats, multilobed nucleus, rapid
turnover, work well under ischemic conditions,
important in the phagocytosis of pathogens
Resting Neutrophils
are round with no fibers

Activated Neutrophils
are flat & form fibers
Neutrophils generate extracellular
Fibers called NETS that kill bacteria
Without the need for phagocytosis.
NETS=neutrophil
extracellular traps

NETS

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 Negative

bacteria associate with neutrophil
fibers-NETs appear to be a form of
innate response that binds microorganisms, preventing them from
spreading and have bactericidal activity

S. Aureus

S. Typhimurium

S. Flexneri

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.
3) Dendritic Cellscells derived from the

bone marrow which are found predominately

in T-cell areas of lymphoid tissue as well as in
the skin. They are phagocytic when they are
immature and they take up pathogens. When
mature they have the capacity to bind antigens
on their surface and are able to present these
antigens to and are effective in activating
resting T-cells & initiating adaptive
immune responses.
c. Other cells
1) Mast Cellsthis resident connective
tissue cell is considered a component of the
immune system. It is found near blood vessels
and contains lots of basophilic granules, the
cells release histamine, and slow reacting
substance of anaphylaxis-->increases vascular
permeability-->edema

Cell Type
Macrophage

Dendritic cell

Neutrophil
Mast
Cell

2. Organs/tissues of the Immune System: Specialized organs and

collections of tissue where lymphocytes interact with non-lymphoid cells,
which are important either to their maturation or to the initiation of
adaptive immune responses.
Lymphatic (Immune) tissues are
characterized by having numerous lymphocytes and significant numbers
of reticular fibers. They are classified as follows:
a. Primary (Central) Immune Organs--where stem cells develop and
differentiate 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 or
pathogens arriving from sites of infection and antigen is presented to lymphocytes
to stimulate adaptive immune responses.
1) Lymph Nodesituated along the extensive drainage system of
lymph 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 provide
an environment in which lymphocytes are able to respond to lymph-borne antigens.
2) Spleenserves as a filter for the blood, it is involved in clearance
and 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; lymphoid
tissue associated with the mucosa of the female reproductive
tract, respiratory tract, etc.
SALTskin-associated lymphatic tissue; lymphatic tissue
associated with the dermis of the skin.

III. Primary Lymphatic Organs:

1. Bone marrow The structure and major hematopoietic
functions of the bone marrow were covered last semester. It
is the second largest organ in aggregate and is the site of
B cell development and maturation.
White Cell Nest

Red Cell Nest

Bone
Marrow

2. Thymus
a. Function/origin: circulating stem cells migrate to the thymus and
differentiate into T-lymphcytes; cells undergo a process of maturation and
education prior to release into the circulation. Embryologically the thymus
originates as an epithelial outgrowth of the third pharyngeal pouch. These
epithelial cells of the pouch form the epithelial reticular cells of the thymic
stroma.
b. Structure: The thymus is covered by an irregular connective tissue capsule
and is divided into lobes that are further separated by thin connective tissue
septa into lobules. The central medulla (core) of each lobule is surrounded by
an outer cortex.

septa

Capsule

Histologically:
1) Cortex-consists mainly of star shaped cells called epithelial reticular cells with
lymphocytes found between the processes of these cells. Because it is loaded with lymphocytes it
stains darkly compared to the medulla (see fig. below). Epithelial reticular cells are connected by
desmosomes 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 the
medulla are larger and form thymic (Hassalls) corpuscles. These are comprised of one or
several central calcified or degenerated epithelial reticular cells, surrounded by flat keratinized
cells in a concentric arrangement.

Epithelial Reticular Cells: There are 6 types (Type I-VI); types I-III are
found in the cortex and derived from the ectoderm; types IV-VI are
found in the medulla and are derived from the endoderm of the 3rd
pharyngeal 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)
Clinical correlation: In certain canine breeds
(e.g. Weimaraners) insufficient levels of growth
hormone cause the thymus gland to develop
improperly. T- lymphocytes that originate in the
thymus mature abnormally, and are not as
effective against viruses, protozoa, and fungi.
Thus these dogs are subject to recurrent
infections. Condition is greatly improved with
growth hormone replacement.

IV. Secondary Lymphatic Organs: Lymphocytes leave the primary lymphatic organs
and 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 and
tightly packed B-lymphocytes) and diffuse extranodular lymphatic tissue (adjacent to
the nodules; contains dense accumulations of small T-cells, macrophages and some
lymphoblasts).

Lymphatic Follicle (Nodule) - Tonsil

Lymphatic Follicle Peyers Patch

Corona

1. Immune tissue associated with various organs

a. Gut-Associated Lymphatic Tissue (GALT): solitary and aggregated lymphatic
nodules associated with the gut including (Peyer's patches, mesenteric lymph nodes and the
appendix). It is especially rich in B-cells and is responsible for localized immunity to pathogens
such as bacteria, viruses, and parasites. The most prominent aggregate of lymphatic nodules of the
GALT is located in the ileum and is called Peyers Patches, (seen grossly as elevations of the
mucosa) present a strong line of defense against invading bacteria, viruses, and other foreign
particles 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.

Lumen

Ileum

Figure 4: Scanning Electron Micrograph of Peyers Patches in the

bovine GI tract.

Clinical Note: Johnes Disease in Cattle: When calves ingest M. paratuberculosis, it

invades the last part of the small intestine and is taken up by M cells associated with
Peyers Patches. Unfortunately for calves, after the M cells bring M. paratuberculosis to
the Peyer's patch and they are engulfed by macrophages, the bacterium finds itself in an
ideal location. Macrophages are efficient microbial killers in most cases. For reasons that
are only partially understood, macrophages fail to kill this kind of bacteria. So the bacteria
replicate, ultimately causing inflammation that impairs intestinal function and causes
diarrhea. The ileum becomes thickened by granulomatous inflammation, and a condition
known as a protein-losing enteropathy occurs (i.e. protein absorption is impaired and
excess 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 or

aggregates of nodules commonly found in the subepithelial connective tissue of mucous
membranes associated with the female reproductive tract, respiratory tract, and urinary
tract.
1) Aggregated lymphatic nodules of the MALT are prominent in the pharyngeal region
where they are referred to as tonsils. They are located adjacent to the lumen of the host
organ and are covered by stratified squamous (oropharynx, see below) or
pseudostratified columnar (nasopharynx) epithelium.
Nasopharyngeal Tonsil

Crypt
Nodule

Secondary lymph tissue associated with other

tissues/organs
b. Mucosa associated (MALT)
Antigens penetrate mucosa and expose lymphatic tissue
2) The epithelium overlying the tonsils is usually infiltrated to a variable degree
with lymphocytes, neutrophils and macrophages
Nasopharyngeal
Tonsil
Lymphocytes invade
overlying epithelium

Clinical Correlation
Abnormalities

Immune Deficiences-Immune deficiency diseases sire a group

of disorders in which normal host defenses against disease are
impaired. These include defects in non-specific host defenses
(e.g., complement deficiency; functional white blood cell
disorders), and defects in specific host defenses (e.g.,
immunosuppression caused by pathogenic bacteria, viruses and
parasites; combined immune deficiency; IgA deficiency; growth
hormone deficiency). Example: Feline Leukemia Virus- a retrovirus,
is the most important infectious disease agent producing fatal
illness in domestic cats today.

Cancer- the cancer itself can be profoundly immunosuppressive.

The form of immunosuppression usually varies with the tumor
type. For example, lymphoid tumors (lymphomas and leukemia)
tend to suppress antibody formation, whereas tumors of T-cell
origin generally suppress cell-mediated immunity

Immune System 1: Lab Introduction

Bone Marrow: Decalcified hyoid bone from a cow

Periosteum

Cortical Bone

Bone Marrow
Bone
Spicule
Spongy
Bone
Fat Cells

Bone Marrow with Granulocytic and Erythroid Cell Nests

Bone
Spicules

Marrow with
Cell Nests

Higher Magnification: Bone Marrow

Megakaryocyte
Erythroid
Cell Nests

Fat Cell

Granulocytic
Cell Nests

Bone Marrow: Granulocytic and Erythroid Cell Nests

Granulocytic cell nest

Erythroid Cell Nest

Developing White (Granulocytic) Cell Nest

Granulocytic Cells

Thymus

Medulla
Cortex

capsule

Thymus: Medulla
Epithelial Reticular Cells

GALT [Ileum]
Lumen

Lymphatic
Nodules

Oropharyngeal
Tonsil

Nasopharyngeal Tonsil
Mantle
Lymph
nodule
Germinal
Center

Nasopharyngeal Tonsil showing

Mucosal invasion by lymphocytes