COMILLA UNIVERSITY

Department Of Pharmacy

Assignment On : Interaction between innate and adaptive

immune system

Course Title : Clinical Pathology

Course Code : PHARM- 3204

Submitted To :
Mantasha Tabassum
Lecturer
Department Of Pharmacy
Comilla University

Submitted By :
Md. Jabedul Alam Sarkar
ID : 11715017
Session : 2016-17
Department Of Pharmacy
Comilla University

Date Of Submission : 30-01-2020

 INDEX
Serial Topics Name Page
No. No.
1. Introduction 1

2. Types of immune system 3

3. Types of barriers of innate immune system 4

4. Components of innate immune system 6

5. Components of adaptive immune system 10

6. Characteristics of adaptive immune system 14

7. Types of adaptive immunity 15

8. Difference between innate and adaptive immune 17

system

9. Communication of innate immune system with 19

adaptive immune system in order to clearout an
infection
10. References 22

11. Conclusion 23
 1. INTRODUCTION :

The immune system is a host defense system comprising many biological

structures and processes within an organism that protects against disease.
To function properly, an immune system must detect a wide variety of
agents, known as pathogens, from viruses to parasitic worms, and
distinguish them from the organism's own healthy tissue. In many species,
there are two major subsystems of the immune system: the innate immune
system and the adaptive immune system. Both subsystems use humoral
immunity and cell-mediated immunity to perform their functions. In humans,
the blood–brain barrier, blood–cerebrospinal fluid barrier, and similar fluid–
brain barriers separate the peripheral immune system from the
neuroimmune system, which protects the brain.

Pathogens can rapidly evolve and adapt, and thereby avoid detection and
neutralization by the immune system; however, multiple defense
mechanisms have also evolved to recognize and neutralize pathogens. Even
simple unicellular organisms such as bacteria possess a rudimentary
immune system in the form of enzymes that protect against bacteriophage
infections. Other basic immune mechanisms evolved in ancient eukaryotes
and remain in their modern descendants, such as plants and invertebrates.
These mechanisms include phagocytosis, antimicrobial peptides called
defensins, and the complement system. Jawed vertebrates, including
humans, have even more sophisticated defense mechanisms, including the
ability to adapt over time to recognize specific pathogens more efficiently.
Adaptive (or acquired) immunity creates immunological memory after an
initial response to a specific pathogen, leading to an enhanced response to
1
subsequent encounters with that same pathogen. This process of acquired
immunity is the basis of vaccination. Disorders of the immune system can
result in autoimmune diseases, inflammatory diseases and cancer.

Immunodeficiency occurs when the immune system is less active than

normal, resulting in recurring and life-threatening infections. In humans,
immunodeficiency can either be the result of a genetic disease such as
severe combined immunodeficiency, acquired conditions such as HIV/AIDS,
or the use of immunosuppressive medication. In contrast, autoimmunity
results from a hyperactive immune system attacking normal tissues as if they
were foreign organisms. Common autoimmune diseases include
Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and
systemic lupus erythematosus. Immunology covers the study of all aspects
of the immune system.(1)

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 2. TYPES OF IMMUNE SYSTEM :

There are two major types of immune system in our body. Such as :
I) Innate immune system
II) Adaptive immune system

I) Innate immune system :

Innate immunity is inherited by the organism from the parents and protects it
from birth throughout life. For example humans have innate immunity against
distemper, a fatal disease of dogs. As its name nonspecific suggests that it
lacks specific responses to specific invaders. Innate immunity or nonspecific
immunity is well done by providing different barriers to the entry of the foreign
agents into our body.

II) Adaptive immune system :

The immunity that an individual acquires after the birth is called acquired or
adaptive or specific immunity. It is specific and mediated by antibodies or
lymphocytes or both which make the antigen harmless. It not only relieves
the victim of the infectious disease but also prevents its further attack in
future. The memory cells formed by cells and T cells are the basis of acquired
immunity. Thus acquired immunity consists of specialized and T
lymphocytes and Antibodies.(2)

3
 3. TYPES OF BARRIERS OF INNATE IMMUNE SYSTEM :

Innate immunity consists of four types of barriers— physical, physiological,

cellular and cytokine barriers.

I. Physical Barriers:
They are mechanical barriers to many microbial pathogens. These are of two
types. Skin and mucous membrane.

(a) Skin: The skin is physical barrier of body. Its outer tough layer, the
stratum corneum prevents the entry of bacteria and viruses.

(b) Mucous Membranes: Mucus secreted by mucous membrane traps

the microorganisms and immobilises them. Microorganisms and dust
particles can enter the respiratory tract with air during breathing which
are trapped in the mucus. The cilia sweep the mucus loaded with
microorganisms and dust particles into the pharynx (throat). From the
pharynx it is thrown out or swallowed for elimination with the faeces.

II. Physiological Barriers:

The skin and mucous membranes secrete certain chemicals which dispose
off the pathogens from the body. Body temperature, pH of the body fluids
and various body secretions prevent growth of many disease causing
microorganisms. Some of the important examples of physiological barriers
are as follows:

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(a) Acid of the stomach kills most ingested microorganisms.
(b) Bile does not allow growth of microorganisms.
(c) Cerumen (ear wax) traps dust particles, kills bacteria and repels insects.
(d) Lysozyme is present in tissue fluids and in almost all secretions except in
cerebrospinal fluid, sweat and urine. Lysozyme is in good quantity in tears
from eyes. Lysozyme attacks bacteria and dissolves their cell walls.
Lysoenzyme is also found in saliva.
(e) Nasal Hair. They filter out microbes and dust in nose.
(f) Urine. It washes microbes from urethra.
(g) Vaginal Secretions. It is slightly acidic which discourages bacterial growth
and flush microbes out of vagina.
(h) Sebum (sweat). It forms a protective acid film over the skin surface that
inhibits growth of many microbes.

III. Cytokine Barriers:

Cytokines (Chemical messengers of immune cells) are low molecular weight
proteins that stimulate or inhibit the differentiation, proliferation or function of
immune cells. They are involved in the cell to cell communication. Kinds of
cytokines include interleukins produced by leucocytes, lymphocytes
produced by lymphocytes, tumour necrosis factor and interferon’s (IFNs).
Interferon’s protect against viral infection of cells.

5
 4. COMPONENTS OF INNATE IMMUNE SYSTEM :

These are certain white blood corpuscles (leucocytes), macrophages,

natural killer cells, complement system, inflammation, fever, antimicrobial
substances, etc.

(i) Certain Leucocytes:

Neutrophils and monocytes are major phagocytic leucocytes.
(a) Polymorpho-nuclear Leucocytes (PMNL- neutrophils): As they have
multilobed nucleus they are normally called polymorphonuclear
leucocytes (PMNLneu- trophils). Neutrophils are short lived and are
highly motile phagocytic killers. Neutrophils are formed from stem cells
in the bone marrow. Neutrophils are the most numerous of all
leucocytes. They die after a few days and must therefore, be constantly

6
 replaced. Neutrophils constitute about 40% to 75% of the blood
leucocytes in humans.
(b) Monocytes: They are the largest of all types of leucocytes and
somewhat amoeboid in shape. They have clear cytoplasm (without
cytoplasmic granules). The nucleus is bean-shaped. Monocytes
constitute about 2-10% of the blood leucocytes. They are motile and
phagocytic in nature and engulf bacteria and cellular debris. Their life
span is about 10 to 20 hours. Generally they change into macrophages
after entering tissue spaces.

(ii) Macrophages:
Monocytes circulate in the bloodstream for about 8 hours, during which time
they enlarge and then migrate into the tissues and differentiate into specific
tissue macrophages. Macrophages are long lived and are highly motile
phagocytic. Macrophages contain more cell organelles especially
lysosomes. Macrophages are of two types,
(a) Some take up residence in particular tissues becoming fixed macroph-
ages and (b) whereas other remain motile and are called wandering
macrophages. Wandering macrophages move by amoeboid movement
throughout the tissues. Fixed macrophages serve different functions in
different tissues and are named to reflect their tissue location. Some
examples are given below:
* Pulmonary alveolar macrophages in the lung
* Histiocytes in connective tissues
* Kupffer cells in the liver
* Glomerular Mesangial cells in the kidney
* Microglial cells in the brain
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* Osteoclasts in bone

(iii) Natural Killer Cells (NK Cells):

Besides the phagocytes, there are natural killer cells in the body which are a
type of lymphocytes and are present in the spleen, lymph nodes and red
bone marrow. NK cells do not have antigen receptors like T cells and cells.
NK cells cause cellular destruction in at least two ways :

(a) NK cells produce perforins which are chemicals that when inserted
into the plasma membrane of a microbe make so weak that cytolysis
(breakdown of cells particularly their outer membrane) occurs and
creates pores in the plasma membrane of the target cells. These pores
allow entry of water into the target cells, which then swell and burst.
Cellular remains are eaten by phagocytes.

(b) Another function of NK cells is apoptosis which means natural cell

death. It occurs naturally as part of the normal development,
maintenance and renewal of cells, tissues and organs. Thus functions
of NK cells are to destroy target cells by cytolysis and apoptosis. NK
cells constitute 5%-10% of the peripheral blood lymphocytes in
humans.

(iv) Complement :
Complement is a group of 20 proteins, many of which are enzyme precursors
and are produced by the liver. These proteins are present in the serum of
the blood (the fluid portion of the blood excluding cells and clotting factors)
and on plasma membranes. They are found circulating in the blood plasma
8
and within tissues throughout the body. They were named complement by
Ehrlich because they complement the actions of other components of the
immune system (e.g., action of antibody on antigen) in the fight against
infection. Jules Bordet is the discoverer of complement. Complement
proteins create pores in the plasma membrane of the microbes. Water enters
the microbes. The latter burst and die. The proteins of complement system
destroy microbes by (A) cytolysis (B) inflammation and (C) phagocytosis.
These proteins also prevent excessive damage of the host tissues.

(v) Inflammation:
Inflammation is a defensive response of the body to tissue damage. The
conditions that may produce inflammation are pathogens, abrasions
(scraping off) chemical irritations, distortion or disturbances of cells, and
extreme temperatures. The signs and symptoms of inflammation are
redness, pain, heat and swelling. Inflammation can also cause the loss of
function in the injured area, depending on the site and extent of the injury.
Inflammation is an attempt to dispose of microbes, toxins, or foreign material
at the site of injury to prevent their spread to other tissues, and to prepare
the site for tissue repair. Thus, it helps restore tissue homeostasis.
Broken mast cells release histamine. Histamine causes dilation of capillaries
and small blood vessels. As a result more blood flows to that area making it
red and warm and fluid (plasma) takes out into the tissue spaces causing its
swelling. This reaction of the body is called inflammatory response.

(vi) Fever :
Fever may be brought about by toxins produced by pathogens and a protein
called endogenous pyrogen (fever producing substance), released by
9
macrophages. When enough pyrogens reach the brain, the body’s
thermostat is reset to a higher temperature, allowing the temperature of the
entire body to rise. Mild fever strengthens the defence mechanism by
activating the phagocytes and by inhibiting the growth of microbes. A very
high temperature may prove dangerous. It must be quickly brought down by
giving antipyretics.(3)

5. COMPONENTS OF ADAPTIVE IMMUNE SYSTEM :

Acquired or, adaptive immunity has two components: humeral immunity or

Antibody mediated immune system (AMIS) and cellular immunity or cell
mediated immune system (CMIS).

10
I. Antibody Mediated Immune System (AMIS) or Humoral Immunity:
It consists of antibodies (specialised proteins produced in the body in
response to antigen) that circulate in the body fluids like blood plasma and
lymph. The word ‘humor’ pertains to fluid. lymphocytes (B cells) produce
antibodies that regulate humoral immunity. The T-lymphocytes themselves
do not secrete anti-bodies but help lymphocytes produce them. Certain cells
of the bone marrow produce lymphocytes and mature there. Since
lymphocytes produce antibodies, therefore, this immunity is called antibody
mediated or humoral immunity. Humoral immunity or antibody-mediated
immune system (AMIS) provides defence against most extracellular bacterial
pathogens and viruses that infect through the respiratory and intestinal tract.

Formation of Plasma cells and Memory cells:

When antibodies on cell’s surface bind antigens (any substances that cause
antibodies formation) the cell is activated and divides, producing a clone
(descendants of a single cell) of daughter cells. These clones give rise to
plasma cells and memory cells. This phenomenon is called clonal selection.

(a) Plasma Cells (Effector cells): Some of the activated cells enlarge,
divide and differentiate into a clone of plasma cells. Although plasma
cells live for only a few days, they secrete enormous amounts of
antibody during this period.
(b) Memory Cells: Some activated cells do not differentiate into plasma
cells but rather remain as memory cells (Primed cells). They have a
longer life span. The memory cells remain dormant until activated
once again by a new quantity of the same antigen.

11
II. Cell-Mediated Immune System (CMIS) or -Cell Immunity:
A healthy person has about a trillion lymphocytes. Lymphocytes are of two
types: T lymphocytes or T cells and lymphocytes or cells. As we know both
types of lymphocytes and other cells of the immune system are produced in
the bone marrow. The process of production of cells of immune system in
the bone marrow is called haematopoiesis. Because T lymphocytes (T cells)
mature in the thymus, this immunity is also called T- cell immunity.

The T-cells play two important functions—effector and regulatory.

The effector function includes cytolysis (destruction of cells by immune
processes) of cells infected with microbes and tumour cells and lymphokine
production. The regulatory functions are either to increase or to suppress
other lymphocytes and accessory cells. Types of T-cells and their Functions:

1. Helper T cells (TH):

TH cells are most numerous of the T cells. They help in the functions of
immune system. They produce a growth factor that stimulates -cell
proliferation and differentiation and also stimulates antibody production by
plasma cells; enhance activity of cytotoxic T cells.

2. Cytotoxic T cells (Tc) or Killer cells:

These cells are capable of killing microorganisms and even some of the
body’s own cells directly hence they are called killer cells. The antigen
receptors on the surfaces of the cytotoxic cells cause specific binding with
antigens present on the surface of foreign cell. Cell after binding, the
cytotoxic T cell secretes hole-forming proteins, called perforins, that punch

12
large round holes in the membrane of the foreign cell. Then fluid flows quickly
into the cell from the interstinal space. In addition, the cytotoxic T cell
releases cytotoxic substances directly into the foreign cell. Almost
immediately, the foreign cell becomes greatly swollen and it usually
dissolves shortly thereafter. Thus they destroy body cells infected by viruses
and attack and kill bacteria, fungi, parasites and cancer cells.

3. Memory T Cells (Primed Cells) :

These cells are also formed by T-lymphocytes as a result of exposure to
antigen and remain in the lymphatic tissue (e.g., spleen, lymph nodes). They
recognize original invading antigens even years after the first encounter.
These cells keep ready to attack as soon as the same pathogens infect the
body again. They proliferate and differentiate into cytotoxic T cells, helper T
cells, suppressor T cells, and additional memory cells.

4. Suppressor Cells (Regulatory T cells (TR)) :

These cells are capable of suppressing the functions of cytotoxic and helper
T cells. They also inhibit the immune system from attacking the body’s own
cells. It is believed that suppressor cells regulate the activities of the other
cells. For this reason, the suppressor cells are classified as regulatory T
cells.(4)

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6. CHARACTERISTICS OF ADAPTIVE IMMUNE SYSTEM :

(i) Specificity: It is the ability to differentiate between various foreign

molecules (foreign antigens).
(ii) Diversity: It can recognise a vast variety of foreign molecules
(foreign antigens).
(iii) Discrimination between Self and Non-self: It can recognise and
respond to foreign molecules (non-self) and can avoid response to
those molecules that are present within the body (self) of the animal.
(iv) Memory: When the immune system encounters a specific foreign
agent, (e.g., a microbe) for the first time, it generates immune
response and eliminates the invader. This is called first encounter.
The immune system retains the memory of the first encounter. As a
result, a second encounter occurs more quickly and abundantly
than the first encounter. The cells of the immune system are derived
from the pluripotent stem cells in the bone marrow. Pluripotent
means a cell that can differentiate into many different types of tissue
cells. The pluripotent stem cells can form either myeloid stem cells
or lymphoid stem cells. Myeloid stem cells give rise to monocytes,
macrophages and granulocytes (neutrophils eosinophil’s, and
basophils). RBCs and blood platelets (lymphoid stem cells) form
lymphocytes (B cells), T lymphocytes (T-cells) and natural killer
(NK) cells.

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 7. TYPES OF ADAPTIVE IMMUNITY:

Acquired (= Adaptive) Immunity is of two types: active immunity and passive

immunity.

1. Active Immunity:
In this immunity person’s own cells produce antibodies in response to
infection or vaccination. It is slow and takes time in the formation of
antibodies. It is long lasting and is harmless. Active immunity may be natural
or artificial.
(a) A person who has recovered from an attack of small pox or measles
or mumps develops natural active immunity.
(b) Artificial active immunity is the resistance induced by vaccines.
Examples of vaccines are as follows: Bacterial vaccines, (I) Live- BCG
vaccine for tuberculosis, (II) Killed vaccines- TAB vaccine for enteric
fever.
Viral vaccines, (I) Live – sabin vaccine for poliomyelitis, MMR vaccine for
measles, mumps, rubella, (II) Killed vaccines- salk vaccine for poliomyelitis,
neural and nonneural vaccines for rabies. Bacterial products. Toxoids for
Diphtheria and Tetanus.

2. Passive Immunity:
When ready-made antibodies are directly injected into a person to protect
the body against foreign agents, it is called passive immunity. It provides

15
immediate relief. It is not long lasting. It may create problems. Passive
immunity may be natural or artificial.

(a) Natural passive immunity is the resistance passively transferred from

the mother to the foetus through placenta. IgG antibodies can cross
placental barrier to reach the foetus. After birth, immunoglobulin’s are
passed to the new-born through the breast milk. Human colostrum
(mother’s first milk) is rich in IgA antibodies. Mother’s milk contains
antibodies which protect the infant properly by the age of three months.

(b) Artificial passive immunity is the resistance passively transferred to a

recipient by administration of antibodies. This is done by administration
of hyper-immune sera of man or animals. Serum (pi. sera) contains
antibodies. For example, anti-tetanus serum (ATS) is prepared in
horses by active immunisation of horses with tetanus toxoid, bleeding
them and separating the serum. ATS is used for passive immunisation
against tetanus. Similarly anti-diphtheric serum (ADS) and anti-gas
gangrene serum (AGS) are also prepared.(5)

16
8. DIFFERENCE BETWEEN INNATE AND ADAPTIVE IMMUNE
SYSTEM :

S.N. Characteristics Innate Immunity Adaptive Immunity

Innate immunity is Adaptive immunity is

1. Presence something already created in response to
present in the body. exposure to a foreign
substance.

2. Specificity Non-Specific Specific

3. Response Fights any foreign Fight only specific

invader infection

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4. Potency Limited and lower High potency
potency

5. Time span Once activated The span of

against a specific type developed immunity
of antigen, the can be lifelong or
immunity remains short.
throughout nthe life.

6. Memory Cannot react with Adaptive system can

equal potency upon remember the
repeated exposure to specific pathogens
the same pathogen. which have
encountered before.

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 9. COMMUNICATION OF INNATE IMMUNE SYSTEM WITH
ADAPTIVE IMMUNE SYSTEM IN ORDER TO CLEAROUT AN
INFECTION :

Microbial infections are recognized by the innate immune system both to

elicit immediate defense and to generate long-lasting adaptive immunity. To
detect and respond to vastly different groups of pathogens, the innate
immune system uses several recognition systems that rely on sensing
common structural and functional features associated with different classes
of microorganisms. These recognition systems determine microbial location,
viability, replication and pathogenicity. Detection of these features by
recognition pathways of the innate immune system is translated into different
classes of effector responses though specialized populations of dendritic
cells. Multiple mechanisms for the induction of immune responses are
variations on a common design principle wherein the cells that sense
infections produce one set of cytokines to induce lymphocytes to produce
another set of cytokines, which in turn activate effector responses.

Here we discuss these emerging principles of innate control of adaptive

immunity. Innate control of adaptive immunity is now a well-established
paradigm. First introduced by Charles Janeway Jr. in 1989, it states that
recognition of conserved features of microbial pathogens by the innate
immune system is mediated by pattern-recognition receptors (PRRs), which
detect conserved pathogen-associated molecular patterns (PAMPs), such
as bacterial and fungal cell-wall components and viral nucleic acids.
Detection of PAMPs by PRRs leads to the induction of inflammatory
responses and innate host defenses. In addition, the sensing of microbes by
19
PRRs expressed on antigen-presenting cells, particularly dendritic cells
(DCs), leads to the activation of adaptive immune responses. Several
classes of PRRs have now been identified and characterized in some detail.
These include Toll-like receptors (TLRs), nucleotidebinding oligomerization
domain (Nod)-, leucine-rich repeat–containing receptors (NLRs), RIG-I-like
receptors (RLRs), C-type lectin receptors (CLRs) and AIM-2 like receptors,
as well as a family of enzymes that function as intracellular sensors of nucleic
acids, including OAS proteins and cGAS2–4.

Fig : Interaction of innate and adaptive immune system

20
The physiological role of different PRRs in the sensing of microbes and the
induction of adaptive immune responses continues to be investigated, but in
general, the available evidence unequivocally supports the view that PRR-
mediated sensing instructs the adaptive immune responses: specifically,
PRRs determine the origin of the antigens recognized by the antigen
receptors expressed on T cells and B cells, as well as determine the type of
infection encountered, and instruct lymphocytes to induce the appropriate
effector class of the immune response.

Studies over the past decade have also revealed several important aspects
of immune system’s function that require an expanded view of the innate
control of adaptive immunity. For example, the type 2 immune response
induced by parasitic worms and allergens appears to be largely independent
of PRRs, perhaps because multicellular parasites lack molecular structures
that are both conserved across different groups of parasites and distinct from
the host organism. Similarly, allergens are not microbial in origin, lack
conserved structural features and induce type 2 immune responses through
mechanisms that remain largely unknown. Another big puzzle is the
apparent ability of the immune system to distinguish between beneficial
commensal microorganisms and pathogenic microorganisms. Both types of
microbes express PAMPs and are detectable by PRRs.
However, the outcome of their recognition can depend on additional
characteristics, such as invasiveness and production of toxins. Recent
progress in understanding the complexity and diversity of commensal
microbiota suggests that perhaps the classic notion of ‘pathogens’ is in fact
applicable only to rare outliers of the entire spectrum of the microorganisms
that can colonize a mammalian host.
21
However, this does not mean that the immune system is concerned only with
these few bad apples; even the normal commensal inhabitants need to be
continuously monitored and somehow ‘managed’ by the immune system to
prevent their outgrowth and mischief. Many discoveries made in the field
over the past decade call for a more complete and nuanced picture of innate
instruction of the adaptive immune responses. Here we review some of the
recent developments in studies of innate control of adaptive immunity.(6)

10. CONCLUSION :

The ability to fend off microbial invasion is critical to our survival. The immune
system is housed in many locations in the body and involves multiple
different organs and cell types. Nonspecific mechanisms, such as intact skin,
mucous membranes, defensins, lysozyme, complement, interferons, natural
killer cells, neutrophils, eosinophils, basophils, and
monocytes/macrophages, constitute a complex first line of defense; these
mechanisms comprise the innate immune system, which is capable of an
immediate response but cannot target a specific pathogen or maintain
immunologic memory. The adaptive immune system, comprised of B-cells
and T-cells (lymphocytes), allows for our immune system to target individual
pathogens and learn from past exposure.
Thus, once we are infected with a certain strain of virus, activation of specific
immunity confers long-term protection against that particular virus. We take
advantage of this secondary response through immunization, and we can
see the problems specificity can have when a self-antigen is labeled as
foreign, leading to autoimmune disease.(4)

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11. REFERENCES :

(1) Informed Health Online. What are the organs of the immune system?
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072579/AccessedJ
uly 11, 2018.

(2) Alberts B, et al. The Adaptive Immune System. In Molecular Biology

of the Cell. New York:Garland Science; 2002.
https://www.ncbi.nlm.nih.gov/books/NBK21070/ Accessed August 2,
2018.

(3) National Institutes of Health. U.S. National Library of Medicine.

Genetics Home Reference. Human leukocyte antigens.
https://ghr.nlm.nih.gov/primer/genefamily/hla Accessed July 4, 2018.

(4) Antigen Presentation. In Cruse JM, Lewis RE, Wang H, eds.

Immunology Guidebook. San Diego: Academic Press; 2004:267-276.

(5) Gabrilovich DI, Nagaraj S. Myeloid-derived-suppressor cells as

regulators of the immune system. Nature Reviews Immunology.
2009;doi:10.1038/nri2506.https://www.ncbi.nlm.nih.gov/pmc/articles/P
MC2828349/

(6) Principles of Innate and Adaptive Immunity. In Janeway CA Jr,

Travers P, Walport M, et al.: Immunobiology: The Immune System in
Health and Disease. New York: Garland Science; 2001.

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