Introduction to Immunology

Our environment contains a great variety of infectious microbes viruses, bacteria, fungi, protozoa
and multicellular parasites. These can cause disease, and if they multiply unchecked they will
eventually kill their host. Most infections in normal individuals are short-lived and leave little
permanent damage. This is due to the immune system, which combats infectious agents. Since micro-
organisms come in many different forms a wide variety of immune responses are required to deal with
each type of infection.
Immunity may be broadly defined as inborn or acquired resistance to disease and involves all of
what may collectively call the host defenses.











Immunology
Any immune response involves
o Recognition of the pathogen/foreign materials.
o Reaction to eliminate it.
Broadly classified as
o Innate (non adaptive)- The resistance which an individual possesses by virtue of its genetic
makeup, non specific, no memory and does not alter on repeated exposure to agent.
o Adaptive (acquired immune response) The resistance that an individual acquires during its
life, highly specific, improves with each successive encounter, remembers the infectious agent
and act fast or prevent the next encounter.
Adaptive immune response is implemented in two ways;
Humoral
Cell mediated

Host Defenses
Specific Defenses
(Immunity)
Innate Immunity
(Inborn)
Accquired Immunity
Naturally Accquried
Active
Such as disease
Passive
Maternal Antibody
Artificially Accquired
Active
Vaccination
Passive
Antisera
(Gamma globulin)
Nonspecific Defenses
(Resistance)
Physical, Cellular, Chemical
and Microbial
In the first instance, the exterior defense of the body presents an effective barrier to most organisms
and very few infectious agents can penetrate intact skin.
Exterior defenses
o Physical barriers to entry of microbes Organisms gain entrance into the body by an active
(penetration of the skin) or passive (ingestion of food and inhalation) means. They have to
pass across physical barriers such as dead layers of the skin, living epithelial cell layers etc.
Many epithelial cells secrete mucus and in the case of nasal passages and bronchi, they have
cilia which beat in an upward direction-remove micro organism (mucociliary escalator).
o Secretions At epithelial surfaces are important in defense. Mucus (mucin) coat their
surfaces and make it difficult for microbes to contact and bind a prerequisite for entry
Site Source Specific substance secreted
Eyes Lacrimal glands (tears) Lysozyme, IgA and IgG
Ears Sebaceous glands Waxy secretion cerumen
Mouth Salivary glands (saliva) Digestive enzymes, lysozyme,
IgA , IgG and lactoferrin
Skin Sweat glands (sweat)
Sebaceous glands (sebum)
Lysozyme, high NaCl
Stomach Gastric juices Digestive enzymes (pepsin,
rennin) acid (low ph, 1-2)

Microbial products and competition Normal commensals (nonpathogenic bacteria), found in skin,
mouth and in the reproductive and gastrointestinal tracts. Symbolic relationship with host and prevent
colonizing of pathogens. (attachment, competing for nutrients and antibacterial sub. Ex colicins, short
chain fatty acids.

Types and basis of immunity and immune response
Innate immune response-First line of defense, having penetrated external defenses, microbes come
into contact with cells and products of the immune system, number of cells and defense molecules
present at the site of invasion or migrate to the site, combat with microbes, present at birth and little
changes throughout the life, first stage of expulsion of the microbe and may give rise to inflammation.

Adaptive immune response- The second line of defense, brought into action while innate immune
system is dealing with the microbe, especially fail to remove invading microbes.

Key difference, latter shows far more specificity and remembers that particular invasion leading rapid
expulsion of same invading microbes in next encounter.






Cells and molecules involved in innate and adaptive immune systems




Adaptive/Acquired immune response








Active immunity is developed by an individual as a result of an infection, antibodies are actively produced
against the microbe (antigens) which is usually long lasting. An individual who has been actively immunized
against an antigen, the respond is very rapid and abundant in the next encounter than during the first invasion.
Natural active immunity results by infectious pathogens by their first encounter and due to actively produced
antibodies and stimulated lymphocytes may be permanent or long lasting duration varies with the type of
pathogen, ex- chicken pox, diphtheria, mumps, and measles. Artificial active immunity is obtained by receiving
vaccines. Vaccination induces the production of antibodies and vaccines are made from living or dead
(inactivated) pathogens or from toxins they excrete.

Passive immunity is a resistance transmitted to a recipient in readymade form. No memory and no antigenic
stimuli are involved, free form of antibodies are administered. Natural passive acquired immunity can be
gained through the placenta to a fetus, or through the colostrums to an infant. Artificial passive immunity can
be obtained by administration of antibodies, ex anti-tetanus.

Characteristics Cells Molecules
Natural Immunity
Responds rapidly
Has some specificity
No memory
Phagocytes (PMNs and
macrophages)
Natural killer cells
Dendritic cells
Cytokines
Complement
Acute phase proteins
Adaptive Immunity
Slow to start
Highly specific
Memory
T and B cells Antibodies
Cytokines
Interaction between innate and adaptive immunity Ex. Macrophages are phagocytic but produce
important cytokines that help to induce the adaptive immune response. Complement components of
the innate system are activated by antibodies (molecules of adaptive system).

Adaptive immune response can be mediated in two ways;
Humoral Antibodies are formed following exposure to specific antigens/pathogens, they specifically
bind with antigen/pathogen and bring about their destruction. The response is to a toxic/foreign
substance outside of the cell -Extracellular
Cell mediated Involves activation of macrophages, natural killer cells, antigen specific cytotoxic T-
lymphocytes (CTL) and directly destroy the infected cells Intracellular











Clonal selection
o Immunocompetent individuals have many distinct lymphocytes. Each of these cells is specific
for a different foreign substance (antigen). When an antigen is introduced into an individual,
lymphocytes with specific receptors seek out and bind with the antigen, causing lymphocytes
to be triggered, proliferated and differentiated into effector cells of immunity. This produces
large number of cells specific to a particular antigen (clone of cells). These cells mediate the
elimination of these antigens or cells produce antigen via interacting them.
o In addition, there are large number of cells being produced along with effector cells known as
memory cells which also specific to the immunizing antigen. These cells remember the
invading antigen and prevent the infection second time by same antigen/pathogen (acting
rapidly for elimination)
o From large pool of B and T cells, antigen selects those which have specific receptors for it and
stimulate their expansion and differentiation into memory and effector cells. B cells can
recognize and bind with native antigen whereas T cells require APC to express antigen on MHC
molecules in order to recognize/interact with the antigen.

Humoral immunoresponse

T- cell dependent antigen


Antigen presenting cells (APCs)
-Process and present antigen through MHC II


MHC II (T
H
CD4)


T cells get triggered by
- Signal from TCR-MHC II complex
-IL-1 produced by APCs


Activated T
H
cells produce IL-2


IL-2 activates B cell stimulation


Activated B cell binds to the antigen and proliferate
(Clonal selection)


Differentiate to effector cells/plasma cells and
Memory cells


Effector cells/Plasma cell produces antibodies specific
to the encountered antigen/pathogen





T-cell independent antigen


B cells recognize/interact directly with antigen
independently (without T cells)


Activated B cell binds to the antigen and proliferate
(Clonal selection)


Differentiate to effector cells/plasma cells and
Memory cells


Effector cells/Plasma cell produces antibodies specific
to the encountered antigen/pathogen





Cell mediated immunity / T-cell mediator
T
c
T cytotoxic cells
Intracellular antigen Viral infections, synthesize viral proteins
Some are degraded to peptide fragments which complex with MHC I

Displayed on the surface of the cells (APCs)/infected cell
-Process and present antigen through MHC I

MHC I (T
c
CD8)

T
c
T cytotoxic cells get activated
-Signal from TCR-MHC I complex
- IL-1 produced by APCs

Activated T
c
start to proliferate

Release cytokines induce apoptosis (IL/interferon/lymphokines)
Perforins- perforation of cell membranes

Destruction of antigens/pathogens


Cells of the immune system
Cells of the immune system derived mainly from undifferentiated cells, self renewing haemopoietic
(HSCs) cells via differentiation
Totipotent haemopoietic cells are found in the yolk sac/liver/spleen/bone marrow/embryo at fetal
stage, after birth and throughout the adult life normally found in bone marrow where they give rise to
four major cell lineages,
o Lymphoid- Lymphocytes
o Myeloid-Mononuclear phagocytes/granulocytes
o Megakaryocytic- Platelets
o Erythroid-Erythrocytes

Platelets produced by megakaryotes and released to circulation.
Granulocytes and moncytes are passed from circulation into tissues.
LGL/NK cells originate from bone marrow and pass into tissues.
B cells mature in the liver and bone marrow in mammals
T cells mature in the thymus.
Cells of the innate immune system

1. Phagocytes - Classified as Mononuclear phagocytes and Polymorphonuclear phagocytes.
Mononuclear phagocytes Polymorphonuclear phagocytes
Monocytes Blood borne precursors of major
tissue phagocytes, macrophages.
Macrophages
Different versions of monocyte-derived
phagocytic cells

Cells Location
Monocytes
Kupffer cells
Mesangial cells
Alveolar macrophages
Microglial cells
Sinus macrophages
Serosal macrophages
Blood stream
Liver
Kidney
Lungs
Brain
Spleen, lymph nodes
Peritoneal cavity

Widely distributed tissue bound phagocytes

Professional phagocytic macrophage- Dispose
of antigens/microbes and dead body cells
through phagocytosis.
Acting as APCs.
Azurophilic granules Enzymes, intracellular
killing of microbes.
Well developed organelles (Golgi, lysosomes).
Receptors for sugar, lipids and IgG and
complement.
Opsonization- A process of making a microbe
easier to phagocytose. Opsonins
(complement component and antibodies)
coat the microbes and aid attachment to the
phagocytes and also trigger activation of
phagocytes.
Neutrophils 95% of the circulating granuloctyes
Multilobe nucleus , diameter 10-20 m
Protein fragments/chemotactic agents attract
Neutrophils easily.
Primary granules- Azurophilic granules; acid
hydrolases/ lysozymes.
Secondary granules-
o Specific , antibiotic proteins
Defesins, cephradine
o Lysozymes
Have surface complement receptors-carry
complexes to liver cells where they are
released and phagocytosed by Kupffer cells.
(important role in clearing immune complexes
from the circulation in persistent infections
and in some autoimmune diseases.

Eosinophils 2-5% of the circulating granuloctyes

Bilobed nucleus, stain with eosin
Phagocytosis, defense the inflammatory
response
Extracellular killing of large parasites (e.g.
schistosome worms)/ via degranulating
contents (peroxides)onto the parasite surface
Release enzymes
o Histaminase, Arylsulphatase limit
granulocyte migration to the
inflammatory sites, attenuate
inflammatory responses. (dampens
the effect of histamine)



2. Lymphocytes - Natural killer cells
Also known as large granular lymphocytes (LGLs), differs from classical lymphocytes-larger, more
cytoplasm, electron dense granules.
Produced in bone marrow, found throughout the tissues of the body, mainly in the circulation,
comprise 5-15% of total lymphocytes.
Surface Fc receptors for IgG and killer activatory receptors (KARs) and killer inhibitory receptors (KIRs)
Kill self cells containing viruses and some tumor cells (activation through KARs). Uninfected cells are
prevented from self killing by negative signaling by KIRs-MHC I molecules complexes (viral infections
reduces inhibitory MHC I expression).
Killing mechanism is identical to that used by cytotoxic T cells (mediated via release of its granule
contents- perforins and granzymes). Perforin has structure similar to that of C9 (complement) which
can punch a hole in the cell membrane, allowing the passage of the granzymes into the cell to induce
apoptosis (NK cells, T cytotoxic cells able to induce apoptosis through surface FasL molecules)











Activated NK cells release IFN upon recognizing virus infected cells-helps to protect surrounding cells
from viral infection. IFN enhance the development of specific T cell responses directed to virus
infected cells.
3. Mast cells and Basophils
Found in connective tissues throughout the body, close to blood vessels and particularly in the sub
epithelial areas of the respiratory, urogenital and gastrointestinal tracts.
Basophils are granulocytes present in very low number in the circulation (<0.2% of granular
leukocytes).
Both are very similar in morphology, have large characteristic electron-dense granules in their
cytoplasm. Like all other granulocytes, basophils are produced from stem cells in bone marrow, origin
of mast cells uncertain probably from bone marrow.
Mast cells/basophils can be stimulated to release their granules as a result of
o Binding to C3a and C5a (anaphylatoxins)
o Crosslinking by IgE antibody and allergens of FcR on their cell surface.
o Binding to lectins (molecules that bind carbohydrates and are found in some fruits)
Activation results in the fusion of the granules with the surface membrane and the release of their
contents to the exterior (exocytosis). Instantaneous and is essential in the development of acute
inflammatory response.
When large number of cells stimulated to degranulate, severe anaphylactic response mildest form
give rise to the allergic symptoms (seen in Type 1 Hypersensitivity)
Granules contain variety of pre-formed pharmacological mediators.
Mediators Effect
Histamine
Cytokines TNF, IL-8, IL-5
PAF(platelet activating factor)
Vasodilation, vascular permeability
Attracts Neutrophils and Eosinophis
Attracts basophils


Platelets

Derived from megakaryocytes, 10
11
platelets production per day, The lifespan of circulating platelets is
5 to 9 days
Upon activation release mediators at the site of a damaged blood vessel Serotonin , fibrinogen
These mediators activate the compliment, which in turn attracts leucocytes to the site of tissue
damage caused by trauma or infection by a parasite.

Cells of the Adaptive immune system
Lymphocytes
Responsible f or the specificity and memory of the adaptive immune responses.
Produced in the primary lymphoid organs and functions in the secondary lymphoid organs/tissues
where they recognize and respond to foreign antigens.
Three types;
o NK cells (involves in innate system),
o T and B cells adaptive system, true antigen specificity and memory.
T cells and B cells mature in thymus and bone marrow, respectively and have similar morphology in
the resting state.
Possess many antigen specific surface receptors and other surface molecules (for activation and for
movement into and out of the tissues). Unique feature ability migrate into tissues and return via
lymphatic vessels to blood stream.

Characteristics of human B and T cells
T cells B cells
Site of maturation

Antigen receptor

Requirement of MHC
For recognition
Thymus

TcR

Yes

Bone marrow

Antibody

No


Characteristic markers



Main location in lymph nodes

Memory cells

Function


Products

All have TcR/CD3
Th-CD4
Tc-CD8

Paracortical area

Yes

Protects against intracellular
microbes

Th1- IFN /TNF
Th2- IL-4, IL-5, IL-6
Tc- Perforins

Surface Ig, CD19/20/21 and
CD79


Follicles

Yes

Protects against extracellular
microbes

Antibodies (B cells mature into
plasma cells)

T lymphocytes
o Control/eliminate intracellular microbes and provide help for B cell (antibody) responses.
o T helper Th help B cell direct cell surface signaling and producing cytokines, consists of TcR and CD3
and CD4 (binds with MHC II), two forms Th1 and Th2
o T cytotoxic (Tc) mediate killing of infected cells (primarily with virus), expresses TcR, CD3 and CD8
(binds with MHC I).
B lymphocytes
o Produced in the bone marrow, like T cells migrate to the secondary lymphoid organs where they
respond to foreign antigens.
o Two types
o B1 cells- arise early in ontogeny, express mainly IgM, mature independently of the bone
marrow, and recognize multimeric sugar/lipid antigens of microbes and T cell independent.
o B2 cells (conventional B cells) Responsible for humoral/antibody mediated immunity,
produced in the bone marrow, and with the help of T cells produce IgG, IgA and IgE.

Dendritic cells

Are so called because of their many surface membrane folds (similar to dendrites of nervous system).
These folds allow maximum interaction with other cells of the immune system, three types;
o Langerhans cells (LH) - Skin
o Interdigitating cells (IDC)- Lymph node T cell areas
o Follicular Dendritic cells (FDC)- B cell follicles of the lymphoid tissues
Present antigens to the lymphocytes, LH and IDC present antigens to T cells. Consists large amounts of
MHC II to present antigens to CD4 T cells (same done by macrophages but LH and IDC more efficient).
These cells are at the interphase of innate and adaptive immune systems. (Recognize microbial
antigens through innate receptors, through endogenous processing pathway enable to present
peptide antigens to T cells).
FDC present within the B cell follicles of lymphoid tissues and hold intact antigens on their surfaces
with which B cells can interact (important in B cells survival within the primary follicles).