HNS204 IMMUNOLOGY

DR. K. MARITIM
 What is Immunology?
Immunology is the biochemical study of body defences
against
 bacteria,

 virus,

 fungi and

 parasites.
 Basic Immunology involves the understanding of
physiochemical properties of substances
(immunochemistry), at level of molecules
(molecular immunology), cells (cellular immunology
)
 Clinical Immunology deals with various immune
mediated diseases including reproductive,
hematological (immunohaematology),
immunodeficiency, infection and immunity,
tumours, graft rejections (clinical transplantation),
allergic, hypersensitivity and autoimmune
associated disorders.
 Immunology is of major value in many areas of
biomedical, clinical, dentistry, pharmacy and basic
sciences.
 In disease diagnosis , immunodiagnostics provide

useful data in treatment and management

including perspectives on underlying
mechanisms within a disease process.
 Confronting challenges of emerging diseases

requires better tooling in immune based

therapies including gene therapy, phototherapy,
use of cytokines and adoptive cell transfer.
 Immunotherapeutical vaccines are also
important in the control of many diseases
particularly conventional vaccines against viral
and bacterial infections.
 Furthermore, Immunology is important in
several other fronts like anthropological studies,
paternity identity and criminal identification
through the employment of DNA and HLA
characterization.
 HISTORICAL PERSPECTIVES
 Scientist(s)---Contribution
 Edward Jenner (1749 – 1823)--Experimented with cowpox

leading to small pox vaccine in 1796

 Louis Pasteur (1822)--Introduced vaccine with the first

attenuated virus vaccine.

 Pasteur (1881 – 1885)--Germ theory led to production of

attenuated vaccines against anthrax, cholera and rabies.

 Ilya Metchnikoff (1845 – 1916)

--Proposed “cellular theory of immunity” involving “phagocytosis”

of “wondering” cells (1884).
 Paul Ehrlich (1854 – 1915 --Believed “humoral
immunity” involving antibodies and not cells.
 Wright and Douglas (1903)

--Demonstrated enhancement of phagocytosis by

serum opsonins indicating a linkage between
humoral and cellular immunity.
 Von Behring (1854-1917) and Kitasato (1870)

--First described diphtheria antitoxin (antibody) –

(1890).
 Robert Koch (1843-1910)
--Described delayed hypersensitivity reaction to
tuberculin (Koch’s phenomenon).
 Buchner (1893)--Described a heat labile serum

factor (complement)
 Bordet (1895) --Demonstrated bacteriolysis of

Cholera vibrio by antibody and complement.

 Ehrlich (1897) --Proposed receptor theory of
antibody synthesis and first described
neutrophils and eosinophils.
 Landsteiner (1900)--Discovered human ABO
blood group system
 Von Pirquet (1874-1929) --Described serum
sickness
 Fleming (1922) --Identified lysozymes
 Tiselius and Kobet (1938) --Demonstrated that
antibody activity resided in the gamma globulin
portion of serum proteins.
 Paul Ehrlich (1892) --Showed maternal transfer
of species specific immunity to infant through
milk.
 Calmette Guerrin (1920) --Developed avirulent
BCG vaccine.
 Colonel Ogden Bruton (1952) --Found
agammaglobulinaemia in a male child.
 Glick and Change (1956) --Observed that
antibody production in chicken dependent on
the presence of the Bursa of Fabricius in birds
 Henson (1739-1774) --Described lymphocytes and
were stained and studied by Paul Ehrlich (1879).
 Holmes et al (1966) --Described phagocytic defect,
chronic granulomatosis disease, in children.
 Doherty and Zinkernagel (1974)--Demonstrated
that T cell recognition of antigen was self –MHC
restricted (1996).
 Susumu Tonegawa (1976)--Discovered that single
immunoglobulin proteins were encoded by
separate rearranging genes (1987).
 Kohler and Milstein (1975)--Discovered the
principle for production of monoclonal
antibodies
 Porter (1950s and 1960s)--Showed
immunoglobulins were composed of two heavy
and two light chains covalently bonded (1950).
 Max Theiler (1938)--Contributed to
development of yellow fever vaccine
 What is immunity?
 “Protection” from infection, tumors, etc.
 Innate immunity is always available
 Adaptive immunity distinguishes “self” from
“non-self” and involves immune system
“education”
 Responses that may result in host tissue
damage
 Defence mechanisms evolved from innate
immunity involving mainly the skin and mucous
to two arms of immune system, humoral and
cellular responses.
CLASSIFICATION OF IMMUNE
RESPONSES
 Innate immunity (not antigen-specific)
 Anatomical barriers
 Mechanical
 Biochemical
 Non-specific (eg. Low pH in stomach)
 Receptor-driven (eg. PAMP-recognition)
 Adaptive immunity (antigen-specific)
 Receptor-driven
 Pre-existing clones programmed to make a specific
immune response (humoral/cellular)
 Antigen
 A substance (antigen) that is capable of
reacting with the products of a specific immune
response, e.g., antibody or specific sensitized
T-lymphocytes.
 A “self” component may be considered an
antigen even though one does not generally
make immune responses against those
components.
Characteristics of Adaptive Immunity
 Immune response is highly specific for the antigen that triggered
it.
 Receptors on surface of immune cells have same specificity as the
antibody/effector activity that will be generated
 Exposure to antigen creates an immunologic “memory.”
 Due to clonal expansion and creation of a large pool of cells committed to
that antigen
 Subsequent exposure to the same antigen results in a rapid and vigorous
response
Components of the immune
system
 platelets
Cells eosinophil
involve megakaryocyte
Pluripotent
T Lymphocyte

d in neutrophil hematopoietic
stem cell
immuni B Lymphocyte

ty common
basophil common lymphoid
myeloid progenit
progenito or
r plasma cell
mast cell
Natural
monocyte Killer cell

macrophage
 Where is that stuff?
Blood
Serum or Leukocytes,
Plasma Platelets and RBC

Mononuclear Polymorphonuclear
Serum Proteins
Cells leukocytes (or
Granulocytes)

•Immunoglobulins •Lymphocytes •Neutrophils

•Complement (T cells, B cells •Eosinophils
•Clotting factors & NK cells) •Basophils
•Many others •Monocytes
 Lymphoid Organs
 Primary or central lymphoid organs
 bone marrow and thymus
 where lymphocytes are generated
 Secondary or peripheral lymphoid organs
 where adaptive immune responses are initiated
Distribution of Lymphoid Tissues
Response to Initial
Infection
Stages of Response to
Infection
 Course
of
Typical
Acute
Infectio
n
Innate Host Defense
Mechanisms
 Geneticdeterminants
 Anatomic Factors

 Mechanical Factors

 Biochemical Factors
 Skin
 Stratified and cornified epithelium provides a
mechanical barrier
 Indigenous microbiota competes with pathogens
 Acid pH inhibits growth of disease producing
bacteria
 Bactericidal long chain fatty acids in sebaceous
gland secretions
 Respiratory Tract
 Upper Respiratory Tract
 Nasal hairs induce turbulence
 Mucous secretions trap particles
 Mucous stream to the base of tongue where material is swallowed
 Nasal secretions contain antimicrobial substances
 Upper respiratory tract contains large resident flora
 Lower Respiratory Tract
 Particles trapped on mucous membranes of bronchi and bronchioles
 Beating action of cilia causes mucociliary stream to flow up into the pharynx
where it is swallowed
 90% of particles removed this way. Only smallest particles (<10µ in
diameter) reach alveoli
 Alveoli
 Alveolar macrophage rapidly phagocytize small particles
 Alimentary Tract
 General defense mechanisms
 Mucous secretions
 Integrity of of mucosal epithelium
 Peristaltic motions of the gut propel contents downward
 Secretory antibody and phagocytic cells
 Stomach
 Generally sterile due to low pH
 Small Intestine
 Upper portion contains few bacteria
 As distal end of ilieum is reached flora increases
 Colon
 Enormous numbers of microorganisms
 50-60% of fecal dry weight is bacteria
 Genitourinary Tract
 Male
 No bacteria above urethrovesicular junction
 Frequent flushing action of urine
 Bactericidal substances from prostatic fluid
 pH of urine
 Bladder mucosal cells may be phagocytic
 Urinary sIgA
 Female (Vagina)
 Large microbial population (lactobacilli)
 Microorganisms produce low pH due to breakdown of glycogen produced by
mucosal cells
 Eye
 Flushing action of tears which drain through the
lacrimal duct and deposit bacteria in nasopharynx
 Tears contain a high concentration of lysozyme

(effective against gram positive microorganisms

 Receptors
 Almost all of biology occurs because recognition
 Enzymatic action
 Interactions between cells (cooperation/activation)
 Communication between cells
 Innate and adaptive immunity requires it
 Innate Immune Recognition
 All multi-cellular organisms are able to recognize
and eliminate pathogens
 Despite their extreme heterogeneity, pathogens
share highly conserved molecules, called
“pathogen-associated molecular patterns”
(PAMPs)
 Host cells do not share PAMPs with pathogens
 PAMPs are recognized by innate immune
recognition receptors called pattern-recognition
molecules/receptors (PRMs/PRRs)
 Typical PAMPs
 Lipopolysaccharides-found in g-ve bacteria
 Peptidoglycans---g+ve bacteria
 Certain nucleotide sequences unique to bacteria
 Other bacterial components
 Ds RNA, ssRNA
 Fungal glucans
 Endogenous Signals Induced by PAMPs

 Mediate inflammatory cytokines

 Antigen-presenting cells recognize PAMPs
 Same APC processes pathogens into specific
pathogen-derived antigens and presents them with
MHC encoded receptors to T-cells
 T-cell responds only when presented with both
signals
 Different Effector Cytokines in Response to Different
Pathogens (Th1 vs. Th2)
 Antimicrobial Peptides/Defensins
 Four hundred peptides described to date
 Defensins (3- 5-kD, four families in eukaryotes)
 -defensins (neutrophils and intestinal Paneth cells)
 -defensins (epithelial cells)
 Insect defensins
 Plant defensins
 Defensins appear to act by binding to outer membrane
of bacteria, resulting in increased membrane
permeability.
 May also play a role in inflammation and wound repair
 Complement System
 Three pathways now known
 Classical
 Alternative
 Lectin or MBL pathway (binding to mannose-
containing carbohydrates)
 Host cells have complement regulatory proteins
on their surface that protect them from
spontaneous activation of C3 molecules
Inflammatory Mediators in Innate Immunity
 Cytokines secreted by phagocytes in response to infection
include:
 IL-1
 activates vascular endothelium and lymphocytes
 Increases adhesiveness of leukocytes
 IL-6
 Induces B-cell terminal maturation into Ig-producing plasma cells
 IL-8
 Induces expression of b2 integrin adhesion molecules on neutrophils, leading
to neutrophil migration to infection site
 IL-12
 Activates NK cells and induces Th1-cell differentiation
 IL-18
 TNF-
 Activates vascular endothelium and increases vascular permeability, leading to
accumulation of Ig and complement in infected tissues
 Other Mediators and Molecules
 Phagocytes
 Toxic oxygen radicals
 Peroxides
 Nitric oxide (NO)
 Lipid mediators of inflammation
 Prostaglandins
 LTB4
 Platelet activating factor
 Complement component C5a
 Stimulates mast cells to release histamine, serotonin and LTB4
 IL-1, IL-6 and TNF-
 Induce acute-phase response in liver
 Induce fever
 IL-1 and IL-18 signaling pathways activate NF- B, important in innate
immunity
Immune Cells and Innate Immunity
 Phagocytes
 Neutrophils
 Monocyte/macrophage
 Eosinophils (to a lesser extent)
 NK cells (large granular lymphocytes)
 Antibody-dependent cell-mediated cytotoxicity (ADCC)
 Have two major functions
 Lysis of target cells
 Production of cytokines (IFN- and TNF-)
 Act against intracellular pathogens
 Herpesviruses
 Leishmania
 Listeria monocytogenes
 Act against protozoa
 Toxoplasma

 Trypanasoma
 Immune Cells and Innate Immunity
(cont’d)
 g/d T cells
 Two types of T cell receptors
 One composed of a and b chains (basic T cell antigen receptor)
 One composed of g and d chains (minor population of T cells)

 Two groups of g/d T cells

 One group found in lymphoid tissues
 One group located in paracellular space between epithelial cells
 Recognizes unprocessed target antigen in absence of APC help
 B-1 cells (minor fraction of B cells, do not require T-cell help)
 Mast cells
 Located in serosa, under epithelial surfaces and adjacent to blood vessels, nerves and glands
 Capable of phagocytosis
 Process and present antigen using MHC class I or II receptors
 LPS can directly induce release of mast cell mediators
 Complement (C3a and C5a) induce mast cells to release mediators
 Chemotaxis, complement activation, inflammation
 TNF-a secreted by mast cells results in neutrophil influx into infected site
 Summary of Innate Immunity

 External and mechanical barriers

 Receptors for pathogen motifs
 Soluble antimicrobial proteins
 Pattern of cytokines produced influences
adaptive response
 TERMINOLOGIES
 Antibody (AB): A protein produced as a result
of interaction with an antigen. The protein has
the ability to combine with the antigen that
stimulated its production.
 Antigen (Ag): A substance that can react with
an antibody. Not all antigens can induce
antibody production; those that can are also
called immunology.
 B cell (also B lymphocyte): Strictly, a bursa–
derived cell in avian species and, by analogy, a
cell derived from the equivalent of the bursa in
non-avian species. B cells are the precursors of
plasma cells that produce antibody.
 Cell – mediated (cellular) immunity:
Immunity in which the participation of
lymphocytes and macrophages is predominant.
Cell–mediated immunity is a term generally
applied to the type IV hypersensitivity reaction.
 Chemokines: low–molecular–weight protein that
stimulate leukocyte movement.
 Chemotaxis: A process whereby phagocytic cells
are attracted to the vicinity of invading pathogens.
 Complement: A set of plasma proteins that is the
primary mediator of antigen-antibody reactions.
 Cytolysis: The lysis of bacteria or of cells such as
tumor or red blood cells by insertion of the
membrane attack complex derived from
complement activation.
 Cytotoxic T cell: T cells that can kill other cells
infected with intracellular pathogens.
 Endotoxins: Bacterial toxins released from
damaged cells.
 Epitope: Site on an antigen recognized by an
antibody. Also known as an antigenic
determinant
 Hapten: A molecule that is not immunogenic
by itself but can react with specific antibody.
 Histocompatible: Sharing transplantation
antigens.
 Humoral immunity: Pertaining to immunity in
a body fluid and used to denote immunity
mediated by antibody and complement.
 Immune response: Development of
resistance (immunity) to a foreign substance
(e.g., infectious agent). It can be antibody-
mediated (humoral) ,cell-mediated (cellular), or
both.
 Innate immunity: Nonspecific resistance not acquired
through contact with an antigen. It includes skin and
mucous membrane barriers to infectious agent and a
variety of non specific immunologic factors, and it may
vary with age and hormonal or metabolic activity.
 Adjuvants: Substances that enhance the immune
response to an antigen when administered along with
that particular antigen
 Adaptive immunity: Protection acquired by deliberate
introduction of an antigen into a responsive host. Active
immunity is specific and is mediated by either antibody
or lymphoid cells (or both)
 Immunoglobulin: A glycoprotein, composed of H and L
chain, that functions as antibody. All antibodies are
immunoglobulin, but not all immunoglobulin have
antibody function.
 Inflammation: Local accumulation of fluid and cells
after injury or infection.
 Interferon: One of a heterogeneous group of low-
molecular-weight proteins elaborated by infected host
cells that protect noninfected cells from viral infection.
Interferons, which are cytokines, also have
immunomodulating functions.
 Leukocyte: General term for a white cell.
 Lymphocyte: A molecule cell 7-12pm in diameter
containing a nucleus with densely packed chromatin and
a small rim of cytoplasma, lymphocytes include the T
cells and B cells, which have primary roles in immunity.
 Macrophage: A phagocytic mononuclear cell derived
from bone marrow monocyte and found in tissues and at
the site of inflammation. Macrophages serve accessory
roles in immunity, particularly as antigen presenting
cells(APCs).
 Major histocompatibility complex(MHC): A cluster
of genes located in close proximity eg, on human
chromosomes 6, that encoded the histocompability
antigens (MHC molecules)
 Membrane attack complex: The end product of
activation of the complement cascade, which contains
C5, C6, C7, and C8 (and C9). The membrane attack
complex makes holes in the membrane of gram-negative
bacteria killing them and, in red blood or other cells,
resulting in lysis.
 Monoclonal antibodies: Each B lymphocyte
produces antibody of a single specificity on
hybridization.
 Monocyte: A circulating phagocytic blood cell
that develops into tissue macrophages.
 Natural killer (NK) cells: Large lymphoid cells
with no known antigen-specific receptors. They
are able to recognize and kill certain abnormal
cells, e g tumor cells.
 Opsonin: A substance capable of enhancing
phagocytosis. Antibodies and complement are
the two main opsonins
 Opsonization: The coatings of an antigen or
particle (e.g., infectious agent) by substances,
such as antibodies, complement components,
fibronectin, and so forth, that facilitate uptake
of the foreign particle into a phagocytic cell.
END