Post on 04-Jan-2016
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www.immunology.unideb.hu
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Esther Bokhobza estherbokhobza@gmail.
com
Self controls: weeks 11th and 14th
MATERIALS CAN BE DOWNLOADED FROM:
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