immunology

BASIC IMMUNOLOGY

PRESENTED BY ADITI SINGH

POST GRADUATE STUDENT DEPARTMENT OF PREVENTIVE AND

PEDIATRIC DENTISTRY SEEMA DENTAL COLLEGE & HOSPITAL

The nomenclature of Immunology

Types of immunity (innate and adaptive; active and passive; humoral and cell-mediated)

Features of immune responses

The major cells of the immune system

Immunity in the oral cavity

Definitions

• Immunity: protection against infections

• Immune system: molecules, cells and tissues that mediate responses to foreign substances

• Antigens: substances recognized by the cells and molecules of the immune system and to which the system responds

Innate immunity: always present (ready to attack); many pathogenic microbes have evolved to resist innate immunityAdaptive immunity: stimulated by exposure to microbe; more potent

Innate and adaptive immunity

The two features that best distinguish adaptive and innate immunity are specificity and memory

Properties of adaptive immune responses

Primary and secondary immune responses illustrate specificity and memory in adaptive immunity

Lymphocytes with highly specific and diverse antigen receptors develop prior to exposure to antigens

The concept of clonal selection

Active and passive immunity

Active immunity: long-lasting protection (memory), multiple effector mechanisms activated, lag time

Passive immunity: rapid protection, short duration

Cells of the immune system

• Lymphocytes– Mediators of adaptive immune responses; only

cells with specific receptors for antigens• Antigen-presenting cells (APCs)

– Specialized to capture, concentrate, and display antigens for recognition by lymphocytes

– Dendritic cells; macrophages, B cells; follicular dendritic cells

• Effector cells– Function to eliminate microbes; include

lymphocytes, granulocytes (neutrophils, eosinophils), macrophages

Congenital immunodeficiency diseases are often caused by blocks at different stages of lymphocyte maturation

Development of B and T lymphocytes

Classes of lymphocytes

The CD Nomenclature

• Structurally defined leukocyte surface molecule that is expressed on cells of a particular lineage (“differentiation”) and recognized by a group (“cluster”) of cell-specific antibodies is called a member of a cluster of differentiation (CD)

• CD molecules (CD antigens, CD markers) are:• Used to classify leukocytes into functionally distinct

subpopulations, e.g. helper T cells are CD4+CD8-, CTLs are CD8+CD4-

• Often involved in leukocyte functions

• Antibodies against various CD molecules are used to:• Identify and isolate leukocyte subpopulations• Study functions of leukocytes• Eliminate particular cell populations

Different types of immune responses are mediated by different classes of lymphocytes and defend against different types of microbes

Types of adaptive immunity

Need for proliferation and differentiation results in delay (typically 4-7 days) in the adaptive immune response

Phases of adaptive immune responses

Stages in the life history of lymphocytes

Proliferation: expands number of antigen-specific cells Differentiation: converts lymphocytes into effective defenders

Naïve, effector and memory lymphocytes

• Naïve lymphocytes– Mature lymphocytes that have not previously

encountered antigen; function -- antigen recognition

– Preferential migration to peripheral lymphoid organs (lymph nodes), the sites where antigens are concentrated and immune responses start

• Naïve lymphocytes– Mature lymphocytes that have not previously encountered

antigen; function -- antigen recognition– Preferential migration to peripheral lymphoid organs (lymph

nodes), the sites where antigens are concentrated and immune responses start

• Effector lymphocytes– Activated lymphocytes capable of performing

the functions required to eliminate microbes (‘effector functions”)

– Effector T lymphocytes: cytokine secretion (helper cells), killing of infected cells (CTLs)

– B lymphocytes: antibody-secreting plasma cells





• Effector lymphocytes– Activated lymphocytes capable of performing the functions

required to eliminate microbes (‘effector functions”)– Effector T lymphocytes: cytokine secretion (helper cells), killing

of infected cells (CTLs)– B lymphocytes: antibody-secreting cells (e.g. plasma cells)

• Memory lymphocytes– Long-lived, functionally silent cells; mount rapid

responses to antigen challenge (secondary responses)





• Effector lymphocytes– Activated lymphocytes capable of performing the functions

required to eliminate microbes (‘effector functions”)– Effector T lymphocytes: cytokine secretion (helper cells), killing

of infected cells (CTLs)– B lymphocytes: antibody-secreting cells (e.g. plasma cells)

• Memory lymphocytes– Long-lived, functionally silent cells; mount rapid responses to

antigen challenge (secondary responses)


M H C MAJOR HISTOCOMPATIBILITY COMPLEX

The histocompatibility antigens are cell surface antigens that induce an immune responses.

In human beings, human leukocyte antigens (HLA) (alloantigens), were found to be the major histocompatibility antigens.

The ability to respond immunologically to an antigen is conditioned by specific genes called the immune response (Ir) genes.

HLA molecules:

HLA class I antigens (A, B and C) are found on the

surface of virtually all nucleated cells.

They are the principal antigens involved in graft

rejection and cell mediated cytolysis.

May function as components of hormone receptors.

HLA class II antigens Are more restricted in distribution -- found only

on cells of the immune system-macrophages, dendritic cells, activated T cells, and particularly on B cells.

HLA class II molecules are primarily responsible for the graft-versus-host response and the mixed leucocyte reaction (MLR)

HLA class III antigens They include complement components linked to the formation of

- C3 convertases.

- Heat shock proteins and

- Tumour necrosis factors.

Many critical interactions among cells of the immune system are controlled by soluble mediators called cytokines.

Cytokines produced by lymphocytes are known as lymphokines, whereas those produced by monocytes or macrophages are called monokines.

Cytokines

-( Interleukins, Interferons, Growth factors)

Types:

Interleukin I (Leucocyte Activating Factor):

-IL -I-, IL-I-

-Stimulation of T Cells

-B cell proliferation, antibody synthesis

-Chemotaxis, Phagocytosis

Interleukin – 2 :(T cell growth factor)

-Powerful Mediator of immune response

Interleukin – 3 :(Multi colony stimulating factor)

-Growth factor for bone marrow stem cells

Interleukin – 4:( B cell growth factor I)

-Growth factor for T cell, mast cells

Interleukin – 5 :(B cell growth factor II)

-Proliferation of activated B cells, Maturation of Eosinophils

Interleukin – 6 :

- Immunoglobulin synthesis

-Stimulatory effects

Colony stimulating factors:

-Stimulates pluripotent stem cells

-Treating haemtopoitic dysfunction

Tumor necrosis factors TNF:

-A serum factor found to induce hemorrhagic necrosis in tumours

-Cachectin, TNF - (activated macrophages)

-TNF - (Lymphotoxin)

Interferons:IFN

-IFN - (Leucocytes)

-IFN - (Fibroblasts)

-IFN - (T cells)

-Macrophage activation

-Antitumour activity

AntigensAntigen (Ag) – the molecule an antibody (Ab) binds to

• usually a foreign substance• each antigen has different sites that antibodies

can bind to, so that one antigen can be bound by several different antibodies

• examples in the case of allergy could be pollen, cat dander, or a chemical in soap

• The two attributes of antigenicity are:

(1) Induction of an immune response

(immunogenicity), and

(2) specific reaction with antibodies.

Complete antigen is able to induce antibody formation and produce a specific and observable reaction with the antibody so produced.

Haptens are substances which are incapable of inducing antibody formation by themselves but can react specifically with antibodies.

The smallest unit of antigenicity is known as the antigenic determinant or epitope.

The combining area on the antibody molecule, corresponding to the epitope, is called the paratope.

ANTIBODY An immunoglobulin

that is capable of combining with specificity to the antigen that elicited its production.Each is made of two identical heavy and two identical light amino acid chains, held together by disulfide bonds

variable regions of the light chain (grey) and the heavy chain (yellow) form the antigen binding site

- light chain constant region is blue while heavy chain constant region is red. The two chains are joined by carbohydrate (purple).

How, Why and Where are Antibodies Produced?

Produced in Vertebrate Cells in response to a ‘non-self’ substance termed an antigen.

The process begins with macrophages roaming in the bloodstream. Macrophages engulf ‘non-self’ molecules and then display portions of the engulfed molecules on their outer plasma membranes.

After many recognition steps B-cells are stimulated to produce specific antibodies.

The antibodies then go off and bind to the foreign substance thereby marking the substance for destruction.

How an Antibody Works

Antibody binds to target antigen

Receptor for constant region of antibody on NK cell recognizes a bound antibody

After binding, the NK cell is signaled to kill the target cell

The target cell dies by apoptosis and/or membrane damage

Primary Response1.Is slow, sluggish and

short-lived, 2.Long lag phase

3.Low titre of antibodies that does not persist for long.

4. Antibody - IgM

SecondaryResponse 1.Is prompt, powerful

and prolonged.2. Short or Negligible lag

phase3. Much higher level of

antibodies that lasts for long periods.

4. Antibody IgG.

IMMUNOGLOBULINS IMMUNOGLOBULIN –’ PROTEINS OF ANIMAL ORIGIN

ENDOWED WITH KNOWN ANTIBODY ACTIVITY AND FOR

CERTAIN OTHER PROTEINS RELATED TO THEM BY CHEMICAL

STRUCTURE’ – WHO (1964)

TYPES DEPENDING ON THE PHYSICOCHEMICAL AND

ANTIGENIC DIFFERENCES

-IgG , IgA, IgM , IgD , IgE

In humans - Peyer's patches develop and lymphoid cells appear

in the spleen and lymph nodes by the 20th week of gestation.

From then on the fetus is able to produce IgM and IgD.

It receives maternal IgG, (but IgA and IgE are not present).

At birth IgM production is enhanced, but IgG level falls steadily,

to reach miminum levels by the 3rd month.

IgG production then picks up and becomes adequate by 2-3

years.

Full immunocompetence is attained only after the first decade

of life.

Stages of development of immunoglobulin

I. IgG Structure: Monomer

Percentage serum antibodies: 80%

Location: Blood, lymph, intestine

Half-life in serum: 23 days

Complement Fixation: Yes

Placental Transfer: Yes

Known Functions: Enhances phagocytosis, neutralizes toxins and viruses, protects fetus and newborn.

II. IgM

Structure: Pentamer

Percentage serum antibodies: 5-10%

Location: Blood, lymph, B cell surface (monomer)


Complement Fixation: Yes

Placental Transfer: No

Known Functions: First antibodies produced during an infection. Effective against microbes and agglutinating antigens.

III. IgA

Structure: Dimer

Percentage serum antibodies: 10-15%

Location: Secretions (tears, saliva, intestine, milk), blood and lymph.


Complement Fixation: No


Known Functions: Localized protection of mucosal surfaces. Provides immunity to infant digestive tract.

IV. IgD

Structure: Monomer

Percentage serum antibodies: 0.2%

Location: B-cell surface, blood, and lymph




Known Functions: In serum function is unknown. On B cell surface, initiate immune response.

V. IgE

Structure: Monomer

Percentage serum antibodies: 0.002%

Location: Bound to mast cells and basophils throughout body. Blood.




Known Functions: Allergicreactions. Possibly lysis of worms.

THE COMPLEMENT SYSTEM Complement was initially described as a substance in peritoneal fluid and

sera that cooperated with antibodies in the lytic destruction of bacteria

(Bacteriolysis Pfeiffer’s phenomenon)

NOMENCLATURE

C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, C9.

Enzymatically active form – C1r

Suffix letters a , b etc represents clevage products

Small intial clevage fragment – ‘a’ fragment

and the large - ‘b’ fragment

eg.C3a, C3b

GENERAL FEATURES

Present in all normal mammalian sera

Complement activation by antibody antigen is possible only with IgM(CH4), IgG1, IgG3(CH2)

Classic activation pathway – cytolytic destruction of membrane sensitive antigens

Alternate pathway (properdin pathway)

Kinin formation, chemotaxis, opsonisation, anaphylotoxin formation and immune adherance

Functions

Lysis- cells, bacteria, and enveloped viruses.

Opsonization- foreign cells, bacteria, viruses are prepared for phagocytosis.

Generation of peptide fragments that regulate features of infammatory and immune responses.

Overview of the Immune Response

IMMUNOLOGICAL TOLERANCE Is the condition in which contact with an antigen specifically abolishes

the capacity to mount an immune response against that particular antigen when it is administered subsequently.

The unresponsiveness of individuals to self antigens was due to the contact of the immature immunological system with self antigens during embryonic life.

Can occur in adults also.

Tolerance may be

- total or partial.

- short-lived or long-lasting.

The induction, degree and duration of tolerance depend on the species and immunocompetence of the host, nature and dose of the antigen and the route of administration.

Immunodifficiency Diseases- Conditions where the defence mechanisms of the body are impaired,

leading to repeated microbial infections of varying severity and sometimes enhanced susceptibility to malignancies

Classification :

a.Primary immunodeficiencies:

-Abnormalities in the development of the immune mechanisms

b.Secondary immunodeficiencies:

-Diseases, drugs, Nutritional inadequacies

Classification of primary immunodeficiency syndrome

A.Disorders of specific immunity

I. Humoral immunodeficiencies (B cell defects)

a.X – linked agammaglobulinemia

b.Transient, hypogammaglobulinemia of infancy

c.Common variable immunodeficiency

d. Immunodeficiencies with hyper IgM

e.Selective immunoglobuin deficiency (IgA, IgM, IgG

II.Cellular immuodeficiencies ( T cell defects)

a.Thymic hypoplasia (DiGeorge’s syndrome

b.Chronic mucocutaneus candidiasis

III.Combined immunodeficiencies(B and T cell defects)

a.Cellular immunodeficiency with abnormal imunoglobulin synthesis(Nezelof syndrome)

b.Ataxia telengictasia

c.Wiskott aldrich syndrome

d.Immunodeficiency with thymoma

e.Immunodeficiency with short- limbed dwarfism

f.Episodic lymphopenia with lymphocytotoxin

B.Disorders of complement

a.Complement component deficiency

b.Complemnt inhibitor defeciencies

C.Disorders of phagocytosis

a.Chronic granulomatos diseases

b.Myloperoxide deficiencies

C.Chediac higashi syndrome

d.Leucocyte G6PD defecie

Secondry immunodeficiencies:

Malnutrition, malignancy, infections, metobolic disorders, cytotoxic drugs

Immunity in the oral cavity

DEVELOPMENT OF ORAL IMMUNE SYSTEMS DURING INFANCY During the mid 1960 s Secretory IgA (SlgA) became

recognized as the primary immune mediator of specific host defenses on mucosal surfaces, specially equipped with four binding sites and secretory component .

during first years of life the infant’s oral cavity receives immune components from several sources :

maternal milk maternal serum ( igg via placental transfer) infant saliva infant serum ( via gcf and teething )

INFANT SALIVARY SOURCES :SALIVARY IgA:

By 4 to 8 weeks of age , saliva from essentially all immunologically sufficient infants contains detectable quantities of IgA .

IgA concentration, yields a peak at about 2 to 3 months. Following this early burst of IgA secretion, salivary IgA concentrations level off during the middle of the first year.

Concentrations then gradually increase through early childhood .Adult levels of salivary IgA are not reached until at least 5 years of age.

Secretory IgA has been identified in the meconium of newborn infants, a substance that is not considered to be maternally derived.

Low concentrations of IgA (and IgM antibody) to poliovirus (PV) and E. coli 0 antigens have also been detected in the saliva of neonates delivered from normal mothers and from mothers with hypogammaglobulinemia.

These antibodies were synthesized in utero to placentally transferred maternal IgG antiidiotypic antibodies to these antigens.

SALIVARY IgG IgG is not considered to be a significant product of adult major

salivary gland tissues.

During fetal life. IgG producing cells are absent from salivary tissue. In the neo natal period, IgG has been found in saliva.Salivary mucosa is temporarily permeable to the nonspecific passage of macromolecules from serum.

The presence of serum-derived IgG in saliva at birth could provide the neonate with passive immunity in the oral cavity because most of this IgG is maternally derived.

However, this source of protection is transitory because salivary IgG concentrations and the percentage of infants in whom these concentrations can be detected rapidly decrease to essentially zero during the first 2 months of life.

IgG then remains absent from the oral cavity until teeth begin to erupt.

SALIVARY IgD Salivary IgD is detected in nearly half of the saliva

samples of children up to 1 month of age.

Salivary IgD detected in these young infants may be locally produced because IgD concentration does not correlate with other salivary components presumed to be serum derived (e.g., IgG and albumin).

The initial elevated frequency of infants with salivary IgD has been reported to fall such that after 5 months of age, IgD could only occasionally be detected in the saliva of children up to 3 years old.

Source : Parotid gland

IgM Like IgA, IgM does not possess the appropriate Fc

configuration to be transferred to the fetus via the placenta.so all IgM in neonatal circulation is synthesized de novo. During the first 1 to 2 months after birth significant concentrations of IgM are present in the saliva

These immunoglobulins exist in much lower concentrations than IgA in these pure glandular secretions

Palatine minor salivary glands are relatively enriched in IgM compared to other major and minor gland salivary glands

THE ORAL CAVITY AS AN IMMUNOLOGICAL ENTITYSALIVARY ENVIRONMENT

Components of Innate Immunity Mucins

Lactoferrin

Salivary peroxidase

Lysozyme

Other Salivary Components-Histidine rich proteins, Proline rich peptides, Beta-2microglobulins & Fibronectin

MUCIN

Mucus secreting cells located mainly in submandibular ,sublingual & minor salivary glands

Lubrication

IgA combines with mucins

Mucin oligosaccharides mimic tissue receptors recognized by bacteria

LACTOFERRIN

Serous cells of salivary gland

PMNs also secrete them

High afinity to Fe

Carboxy anion interaction with bacterial surface

OH- radical generation

SALIVARY PEROXIDASES

PAROTID + SUMBANDIBULAR.,PMNs

H2O2 , Thiocyanate ions

Hypothiocyanate ions

LYSOZYME (muramidase)

Ductal epithelium

N-acetyl muramic acid + N-acetylglucoseamine linkage of peptidoglycan layer of bacterial cellwall is cleaved

COMPONENTS OF THE ANTIBODY MEDIATED IMMUNITY

Secretory IgA

-Stable complexes

-Virus Neutralization, Immune exclusion, ‘Disposal’ of bacteria

-Bacterial Enzyme Inhibition

IgM

- ‘IgM COMPENSATION’

-Opsonization, Complement mediated Lysis

IgG & IgD

-Occurs in low conc.

Another function associated with SIgA activity is bacterial enzyme inhibition.

Salivary IgA antibody has been shown to inhibit the function of a group of enzymes (glucosyltransferases) from cariogenic mutans streptococci that synthesize glucans involved in plaque formation.

Inhibition of this process may also change the diffusion characteristics of plaque, thus allowing bacterial acids to diffuse more readily out of plaque.

SIgA antibody could interfere with bacterial metabolism by inhibiting enzymes involved in transport phenomena.

GCF ENVIRONMENT CELLULAR COMPONENTS

Polymorhonuclear neutrophils -Realeses Granules containing LYSOSOMAL ENZYMES Lymphocytes -B & T Lymphocytes (1%-2%) Monocytes & Macrophages -Supplement the antibacterial activity of PMN Others -Lipopolysaccharides -Bacterial proteases -Prostaglandins

Immunoglobulins:(IgG, IgA, IgM)

Complement:(C3, C4:Additional activated components During disease)

COMPLEMENT In periodontally healthy subjects, C3 and C4 can be

detected.

If inflammation occurs, concentrations of GCF C3 and C4 decrease with respect to serum, and activated complement components such as C3a, C3b, and C5a appear, indicating that complement activation has occurred in the gingival crevice.

This activation is likely to be in response to the increased bacterial load associated with the inflammation. Both classic and alternate complement pathways can be activated.

The biologically active polypeptides released by complement activation have a variety of antibacterial eftects.

PMN’s

In the GCF environment PMNs defend against bacterial invasion of the gingival tissue through phagocytic and bactericidal mechanisms.

The activity of PMNs results in the release of granules containing lysosomal enzymes that can disengage bacterial plaque adherent to the tooth.

These enzymes also have the potential to damage host tissue if present in high enough concentrations.

LYMPHOCYTES , MONOCYTES MACROPHAGES

Both T and B lymphocytes appear in the GCF, comprising 1 % to 2% of the cells found therein.

Approximately three times as many B cells as T cells are present in GCF, which is the converse of their ratio in blood.

Monocytes and macrophages: Approximately 2% to 3% of the remainder of the immune cells in the GCF are monocytes. These cells may supplement the antibacterial activity of the PMNs

IMMUNOLOGICAL ASPECTS OF DENTAL CARIES

At least six species of microorganisms constitute this mutans group. The two most prominent species in humans are S. mutans (serotypes c, e, and f) and Streptococcus sobrinus (serotypes d, g, and h).

Most individuals are colonized by mutans streptococci of the c serotype.

High levels of serum IgG antibody to mutans streptococcal cells or antigens are associated with low levels of caries in young adults. Serum antibody from caries-free young adults inhibits Glucosyltransferases from mutans streptococci to a greater extent than serum from caries-prone individuals.

Studies suggested that low numbers of mutans streptococci in dental plaque are associated with relative elevations in serum IgG antibody in children approximately 2 to 5 years old.

Serum IgG antibody to mutans streptococcal antigens is associated with lower caries experience.

CARIES VACCINE : “Wagner” was the 1st person to successfully vaccinate rats against caries. Interestingly S. fecalis was used as the immunogen

SYSTEMIC ACTIVE IMMUNIZATION Gregory and Filler observed that ingestion of a

vaccine containing killed Streptococcus mutans daily for ten consecutive days induced an increased level of specific secretary IgA antibodies to Streptococcus mutans cells.

This resulted in reduction in number of viable Streptococcus mutans organism in dental plaque and whole saliva

SYSTEMIC PASSIVE IMMUNIZATION Michalek, et al. used a multivalent vaccine

consisting of whole cell antigen of Streptococcus mutans (serotype a, b, c, d, g), to hyperimmunize a group of pregnant cows.

They observed low plaque scores decreased number of streptococci in plaque and decreased caries actually as compared to the control.

Role of Probiotics …..

HYPERSENSITIVITY

CONCLUSION STUDENT- It is dry .It goes above head .It is difficult to

understand.

RESEARCH SCIENTIST- when I don’t know the cause ,I put the blame on immunology.

PRACTITIONERS- I use it as a weapon to escape when my treatment fails.

But actually it is a war between the pathogens and the host defense system which ends in the “SURVIVAL OF THE FITTEST” .

conclusion Immune system is a complex functioning

system Acting against various invading pathogens and preventing the diseases – protective

Helpful in various diagnostic investigations

Acting against the own body tissues – destructive.

IMMUNE SYSTEM , THUS COULD BE A

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