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Esther Bokhobza estherbokhobza@gmail.

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WHY IMMUNOLOGY FOR PHARMACISTS??

Agents acting on the Immune system:

- Non-steroidal anti-inflammatory drugs (NSAIDs)

- Antihistamines- Salicylates- Immunomodulation; drugs that activate or

suppress the immune system

KEEP IN MIND.. 1. MANY ANTI-INFLAMMATORY DRUGS ARE AVAILABLE OVER THE COUNTER SO THERE IS A POTENTIAL FOR ABUSE AND OVERDOSING.

2.PATIENTS ON ANTI-INFLAMMATORY DRUGS BLOCK THE SIGNS AND SYMPTOMS OF A CONDITION, SOMETIMES, MAKE IT HARD TO CORRECTLY DIAGNOSE.

3. PATIENTS MIGHT COMBINE THESE DRUGS AND UNKNOWINGLY INDUCE TOXICITY.

NSAIDS

Flurbiprofen Ibuprofen

Naproxen Diclofenac

Mesalazine / Mesalamine ASA

SALICYLATES

IMMUNOSUPPRESSANT DRUGST CELL INHIBITORS AND ANTI-PROLIFERATIVE DRUGS

Cyclosporin

Tacrolimus

Azathioprine

Cyclophosphamide

Methotrexate

Mycophenolate mofetil

Sirolimus/Rapamycin

IMMUNOSUPPRESSANT DRUGSGLUCOCORTICOIDS

Methylprednisolone

Prednisolone

BetamethasoneBudesonid

eTriamcinolo

ne

IMMUNOSUPPRESSANT DRUGSANTIHISTAMINS

Loratadin Desloratadine Dimetindene

IMMUNOSUPPRESSANT DRUGSLEUKOTRIENE ANTAGONISTS

Montelukast Zafirlukast Zileuton

MONOCLONAL ANTIBODIES

Efalizumab Rho (D) immunoglobin

BasiliximabDaclizumab IL-2R antagonists

IMMUNOSTIMULANT DRUGS

ImiquimodIL-2

Peginterferon alpha 2b

Peginterferon alpha 2a

We live in a potentially hostile world filled with infectious agents of diverse shape, size and composition which would

very happily use us as rich sanctuaries…

…had we not developed a series of defense mechanisms.

These defense mechanisms establish a state of IMMUNITY and are the basis for our delightful subject of ‘IMMUNOLOGY’

Immunitas = freedom from (Latin)

What is the function of the immune system?

What about its specificity? Harmful/ Harmless The detection of stress and danger signals

Innate arm of the immune system

Self / Non-self The differentiation between self and non-self Adaptive arm of the immune system

What about flexibility? (Influenza ex.)Speed? Is there room for failure? (Immunodeficiency)

Keep in mind:

Harmful self, like tumors!Harmless non-self, like normal flora!

- nonspecific- immediate reaction- does not improve- no memory

- highly specific- developes in several days- improves after exposure- has memory

Immune system

Innate / Natural

Acquired / Adaptive

Cellular Granulocytes Monocytes/Macrophages Natural Killer cells Dendritic cells Mast cells

CD4+ (helper) T cells CD8+ (cytotoxic) T cells B cells Plasmacells

Humoral Complement proteins Cytokines Acute phase proteins Antimicrobial proteins

Antibodies

Pathogens win the battle in the absence of either the innate or the adaptive arm of immunity

Innate immunity is often successful in eliminating pathogens. However, it is not sufficient for survival

SCID (severe combined immunodeficiency)“The bubble boy disease”

Facing life-threatening infections

HEMATOPOESIS

IMMUNE CELLS

Production site

Fetal life: yolk sac, liver, spleen

After birth: epiphysis, flat bones, red bone marrow (sternum, ribs, vertebras, skull, pelvis and femurs)

Blood cells are short-lived and have to be continuously renewed,

hematopoiesis is active throughout life.

Leukocytes derive from a common progenitor-the pluripotent hematopoietic stem cell (HSC)

…giving rise to the erythroid, myeloid and lymphoid progenitors

Polymorphonuclear leukocytes (PMNs) / The granulocytes

NEUTROPHIL GRANULOCYTES

EOSINOPHIL GRANULOCYTES

-Main participants in inflammatory processes against extracellular invaders- 68% of circulating leukocytes, 99% of circulating granulocytes- Phagocytic cells- Able to migrate and eliminate pathogens in infected tissues (chemotaxis). Non-dividing, short-lived cells.- Predominant cells in pus

- Involved in parasite defence and allergic reactions- 2-3% of leukocytes

BASOPHIL GRANULOCYTES- 1% of circulating leukocytes- Large granules in the cytoplasm- nucleus with 2 lobes- Like mast cells, secrete histamine and proteolytic enzymes- High affinity IgE receptors- Involved in parasite defence and allergic reactions

12-15 μm2-5 lobes

Unstained granules

2 lobesDark blue granules

Usually 2 lobesBright red granules

Monocytes, Macrophages and Dendritic cells

MONOCYTES

- Circulating cells of the myeloid lineage

- Give rise to macrophages (Mφ) and dendritic cells (DCs)

- Phagocytic cells

- Together with macrophages, form the so called

‘mononuclear phagocyte system’.

MACROPHAGES

- Phagocytic and antigen presenting cells

- Part of the innate immunity but also initiates the activation of adaptive immune response- main types (based on tissue localization):

a) microglia - brainb) Kupffer cells -liverc) histiocytes -connective tissued) osteoclasts -bonee) alveolar macrophages -lung

In Greek Makros=large phagein=eat “big eaters”

10-15 μmBean-shaped nucleus

21 μm

DENDRITIC CELLS

- Antigen presenting and phagocytic cells

- Part of the innate immunity and also act as cellular messengers initiating an adaptive

defence.

- Resting dendritic cells circulate or reside in tissues, sense the environment, are able

to differentiate into mature dendritic cells and migrate further to lymphoid organs to

prime T cells. In Greek Dendros= tree ! Do not mistaken them with dendrites (neuron projections)..

Types :

a) myeloid DCs: - Langerhans cells (mucosa, skin) - interstitial DCs (liver, spleen, etc.)

b) lymphoid DCs: - thymic DCs - Plasmacytoid DCs (pDC): Type I interferon producing cells.

Follicular DCs: Stromal cells of the lymph nodes, found in primary and secondary follicles. similar in appearance but are not of hematopoietic origin.

MAST CELLS

- Tissue resident cells, absent from the circulation

- Cytoplasmic granules containing vasoactive amins e.g. heparin

- Found around small vessels, regulating the vascular permeability

- High affinity cell surface FcεRI receptors, surface covered by IgE

- Defence and healing functions acting both in innate and adaptive immunity

- main types: a) mucosal

b) connective tissue

- Plays a role in the patho-physiology of immunity against helminths and allergic

reactions

- Mature in bursa equivalent tissues*(embrionic liver, later bone marrow)

- 5-10% of the circulating lymphocytes. - Migrate from the bone marrow to the secondary lymphatic organs- Express antigen-specific receptor on their surface (BCR)- Professional antigen presenting cells (APC) - Activated with antigens, interacting with T lymphocytes, lymphokines and cytokines- Upon activation they differentiate to plasma cells and memory B cells

*‘B’= Bursa-derived cell, first described in the hematopoietic organ called Bursa de Fabricius in birds

B LYMPHOCYTES

PLASMA CELLS

- Antibody production- Humoral immune response

-Mature in the thymus where they become mature naive

T cells and they migrate to peripheral (secondary) lymphoid

organs- Express antigen-specific receptor on their surface (TCR)

-types:

- CD4+ T helper (Th1 & Th2)

- CD8+ T cytotoxic (Tc)

- Regulatory T cells (Treg)

T LYMPHOCYTES

NK CELLS(natural killer cells)

- origin: lymphoid progenitors, however, is a participant of the innate immunity.

- They play a role against intracellular infections by killing infected cells. - Granules in their cytoplasm contain perforin and granzymes.- Has no antigen-specific receptors („null cells”) - Recognize abnormal cells (altered proteins and the absence of MHC class I).- Functionally similar to cytotoxic T cells

NK cells

The localization of blood cells

Relative abundance of leukocytes in peripheral blood

Cell type Proportion of leukocytes (%)

NeutrophilLymphocytesEosinophilBasophilMonocyte

40-7520-501-6<12-10

- nonspecific- immediate reaction- does not improve- no memory

- highly specific- developes in several days- improves after exposure- has memory

Immune system

Innate / Natural

Acquired / Adaptive

Cellular Granulocytes Monocytes/Macrophages Natural Killer cells Dendritic cells Mast cells

CD4+ (helper) T cells CD8+ (cytotoxic) T cells B cells Plasmacells

Humoral Complement proteins Cytokines Acute phase proteins Antimicrobial proteins

Antibodies

Professional phagocytic cells

1. Dendritic cells2. Macrophages3. Neutrophil granulocytes

Professional antigen presenting cells (APCs)

1. Dendritic cells2. Macrophages3. B lymphocytes

Pathogens are processed by APCs, their degradation products (peptides) are presented to T lymphocytes on MHC molecules

INNATE IMMUNITY

- immediate reaction- nonspecific- Does not improve after exposure- no memory

ADAPTIVE IMMUNITY

- developes in several days- highly specific- Improves after exposure- has memory

communication

Coordinated and regulated actions of both arms of the immune system

A P C T

Direct communicationvia adhesion molecules

Indirect communicationvia cytokines

OR

MOLECULES OF THE IMMUNE SYSTEMCell surface molecules:- Receptors (e.g. PRRs, BCR, TCR, cytokine receptors, etc.)

- MHC molecules (MHC I, MHC II)

- Co-stimulatory molecules (B7, CD40)

- Adhesion molecules (integrins, selectins, addressins, etc.)

Soluble molecules:- Cytokines (interferons, interleukines, chemokines)

- Antibodies

- Complement components

- Acute phase proteins

The main types of cell surface molecules participating in antigen recognition and

the interaction between dendritic cells and T cells

The most important mediators of indirect cell communication in the immune system („hormones” of the immune system).

Act in low concentrations.

The responsiveness of the given cell is based on the expression of cytokine-specific receptors.

THE MOST IMPORTANT FEATURES OF CYTOKINES

hormonescytokines

chemokines

interleukines

monokines lymphokines

interferons

MHC

IL-1

bakteriálisendotoxin

makrofág

T-sejtTCR

citotoxicitás monokinek adhéziós molekulák

aktiváció IL-2R limfokinek

prosztaglandinok lázaluszékonyságfájdalomküszöb fogyás

autokrin parakrin

end

okrin

THE EFFECTS OF CYTOKINES

PRR ligand

helps activation

fever

helps activation

T cell

macrophage

autocrine paracrine

end

ocri

ne

INTERLEUKINES (IL-1, IL-2, IL-4, IL-6, IL-10, IL-12, TNFα)control functions of leukocytescommunication between leukocytes

CHEMOKINES (IL-8, CCL21)inducing chemotaxisincreasing adhesionactivating leukocytes

TYPE I INTERFERONS (IFNα, IFNβ)parts of innate immunityimportant role against viral infections

producers: infected cells, plasmacitoid DCs

TYPE II INTERFERON (IFNγ)main activators of macrophagesproducers: Th1, CD8+, NK cells

CYTOKINES

Plasma factor can affect different parts of the immune system and vise versa

Carbohydrates (glucose)Lipids (cholesterol, triglycerid, phospholipid, lecitin, fat)Proteins (globulin, albumin, fibrinogen) GlycoproteinHormones (gonadotropin, erytropoetin, thrombopoietin)Amino acidsVitamins (over and malnutrition)

BIOACTIVE MOLECULES INFLUENCE THE ACTIVITY AND FUNCTION OF THE IMMUNE SYSTEM

Professional

phagocytic cells

Neutrophil granulocytes (No presentation of Ag on MHC II)

Professional

antigen presenting cells

B lymphocytes(no killing action, only Ag presentation)

Macrophages

Dendritic cells