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					Cytokine : Hormone interrelationship
R A Holding DO

April 2005

Ark International Training Seminars

Cell communication - The basis of life
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For the smooth operation of all physiological processes in the organism, all of the approximately 60 trillion cells of the body need to be able to communicate. This complex communication occurs via two chemical substances:• Cytokines • Cell surface molecules.

April 2005

Ark International Training Seminars

Cell communication - The basis of life
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This communication occurs as a:
• direct communication:
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adhesion molecules (cell-to-cell contact)

• indirect communication:
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cytokines (messenger substances) bound to specific receptor sites.

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These types of communication take place concomitantly and may also have an influence on one another.
Ark International Training Seminars

April 2005

Immune and endocrine system reciprocity
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April 2005

The cells of immune and neuroendocrine systems share signal molecules and receptors Both hormones and neuropeptides alter function of the immune system Immune system is innervated by noradrenergic sympathetic nerve cells that have direct contact with lymphocytes and macrophages In turn, the immune system-derived cytokines influence the function of both neural and endocrine systems
Ark International Training Seminars

Stress, physiology & function
Emotional stress Environmental stress Xenobiotics

Physiology / Function
Nervous system Immune system

Endocrine system
April 2005
Ark International Training Seminars

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Local inflammatory response

Overview of inflammation:

• Macrophages and monocytes initiate acute phase response (APR) • The APR initiates 1st phase of inflammatory cytokines
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• They activate the 2nd phase of cytokines that augment the shift in balance necessary for the inflammatory response
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April 2005

IL-1 TNF-a

IL-12 INF-a INF-b GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor) Fibroblast growth factor
Ark International Training Seminars

Hormonal stimulation of pro-inflammatory cytokines
Immune system Hypothalamic-pituitary-adrenal axis

at inflammatory sites: secretion of : 1st TNF-a 2nd IL-1

3rd IL-6 which feedbacks to inhibit TNF-a and IL-1

April 2005

stimulated by catecholamines Ark International Training Seminars

low oestrogen increases pro-inflammatory cytokines

Control of the immune reaction
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The specific control of the sequence of the activating and the suppressive steps in the of the immune response is mediated by the immune cells through the release of both proinflammatory and anti-inflammatory cytokines.
The ratio of Th1 (pro-inflammatory) and Th2 (antiinflammatory) cells and their cytokines is clinically important. • They balance each other by inhibiting each other and stimulating their own response

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April 2005

Ark International Training Seminars

Pro-inflammatory Th1 cells and their cytokines
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Th1 cells are pro-inflammatory and are a response to intracellular organisms such as viruses, bacteria and some parasites Inhibition of Th1 leads to failure to respond to infection and to kill cancer cells Chronic stimulation of Th1 leads to autoimmune disease and chronic inflammation

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Th1 dominant diseases include:
• Hashmoto’s disease • Type 1 diabetes • Multiple Sclerosis • Crohn’s disease • Sarcoidosis These activating cytokines are: TNF, IL-1b, IL-2, IL-6, IL12, IFN-a, IFN-, TGF.
Ark International Training Seminars

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April 2005

Anti-inflammatory Th2 cells and their cytokines
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Th2 cells are anti-inflammatory and are a response to helminth parasites and allergens Chronic stimulation of Th2 leads to chronic allergic response and failure to respond to infection and cancer cells

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Th2 dominant diseases include:
• Allergies / atopy • Inflammation The Th2 or anti-inflammatory or suppressing cytokines are: IL-4, IL-5, IL-10, and to some extent IL-13
Ark International Training Seminars

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April 2005

Inflammatory triggers
target cell killing Vasopressin Substance P CRH Prolactin + IL-2 IL-12 + IL-15 INF- IL-2 IL-6 INF-  NK cell CD8 cytotoxic

inflammatory stimulus

Th1 CD4 IL-2 + IL-1 TNF-a   IL-12 IL-2 IL-12 + IL-15 INF-

+
macrophage T-cell

B cell

CD8 cytotoxic IL-4 Il-10 Il-13 + IL-14 IL-3 IL-4 +

IL-4 + TNF-a + IL-1 + IL-12 + IL-10 GM-CSF + Th2 CD4 IL-4 IL-10 -

IL-4 +

Mast cell

IL-5 +

eosinophil
April 2005

vasointestinal peptide melanocyte stimulating hormone Ark International Training Seminars somatostatin +

Control of the immune reaction
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The defensive posture can be:
• excessive in part
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• inhibited in part
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extreme antigen exposition over-stimulation lacking counter regulation
over-expression of immune complexes, cytokines and/or adhesion molecules).

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The over and under expression will impedes the immune functions or causes such systemic side effects as, for example, the wasting syndrome seen in HIV infections. The immune system then recognises endogenous structures as being foreign (cross-reactions, insufficient tolerance).
• This is considered to be the cause of autoimmune diseases. The immune system can react excessively to harmless substances (insufficient tolerance) with the subsequent development of allergies.
Ark International Training Seminars

April 2005

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The immune cells secrete numerous soluble and, in part, highly specialised mediators which, in a series of complex interactions, guarantee for the viability, development, differentiation, proliferation and activity in the organism. These cytokines are soluble glycoproteins that function as intercellular signalling molecules.
• The other three intercellular signalling molecules are neurotransmitters, endocrine hormones and autacoids

Types of cytokines

April 2005

Ark International Training Seminars

Cytokines
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Cytokines have an effect on all cells (not only on the immune cells). Cytokines maintain a rigidly controlled communication network between the individual cell types including those of the nervous system. Cytokines are released in the course of normal cell functions, especially in response to particular stimulus: e.g. antigens, immune complexes, complement, enzymes, other cytokines.
Ark International Training Seminars

April 2005

Control of the immune reaction
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In contrast to the reactions seen with many hormones, those attributed to cytokines usually only involve local, short-distance signals. Normally, their release is usually only necessary for a definite purpose, at a defined time and at a locally-limited site.
Ark International Training Seminars

April 2005

Cytokines

Proinflammatory cytokines

Anti-inflammatory cytokines

up-regulation of the inflammatory response IL-1 IL-6 TNF- a IFN- a IFN- b stimulation of proinflammatory cytokines IL-12
April 2005

TGF-b inhibits T cell proliferation, chemoattractant enhances collagen IL-8 production and facilitates the isolation of the inflammatory Ark International Training Seminars focus

up-regulation of acute phase reactants IL-1 IL-6 IL-11 TNF- a IFN-  TNF- b

inhibition of proinflammatory cytokines IL-4 IL-6 IL-13 Inhibition of NO synthase activity IL-10

Cellular inflammation: triggers
Cell type
B-lymphocyte

Trigger
ACTH, b-endorphins, growth hormone, IGF-1 ACTH, b-endorphins, growth hormone, IGF-1, prolactin, TSH Kinins, vasoactive intestinal peptide, somatostatin
Ark International Training Seminars

T-lymphocytes

Mast cells, eosinophils, neutrophils
April 2005

Cellular inflammation: triggers
Cell type
Platelets
Splenocytes Thymocytes Macrophages
April 2005

Trigger
Serotonin, PAF, neuropeptide-Y LH, FSH, CRH, prolactin CRH, LHRH, AVP, oxytocin ACTH, b-endorphins, growth hormone, substance P

Ark International Training Seminars

Cellular inflammation: neuroendocrine regulation
Cytokine TNF type (TNF-a, TNF-b, IL-1) Effect ↑ type 1 APR ↑ CRP ↑serum amyloid protein ↓ type 2 APR ↑ type 2 APR ↑ fibrinogen ↑ APR Synergy with most cytokines Angiostatic ↓ cytokine effects
Ark International Training Seminars

IL-6 type (IL-6, IL-11) Corticosteroids

Insulin

FGF, TGF-b April 2005

↓ cytokine effects

TNF type cytokines
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TNF-a, TNF-b, IL-1)
• They have the effect of increasing type 1 acute phase reactants (APR), increasing CRP and serum amyloid protein and decreasing type 2 APR • i.e. they assist in the pro-inflammatory response • They increase ACTH • They have a variable effect on prolactin except for IL-6 that increases prolactin • They lower the production of growth hormone, TSH and LH

April 2005

Ark International Training Seminars

Hormonal effects on inflammation
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Corticosteroids increase acute phase reactants (APR), support the action of most cytokines and are angiostatic IL-1a, IL-1b, TNF-a, IL-2 and IL-6 increases ACTH production Insulin decreases the action of most cytokines FGF and TGF-b decrease the action of most cytokines

April 2005

Ark International Training Seminars

Cytokine & effects on hormones
cytokine ACTH
IL-1a IL-1b TNF-a ? ↑ ↑ ↑ ↑ ? ? ↑

prolactin Growth TSH hormone
↕ ↕ ↕ ↑ ↑ ? ↓ ↕ ↓ ↓ ↑ ↑ ↓ ?

LH
↓ ?

FSH
↕ ?

IL-2
IL-6 INF- TGF-b PDGF
April 2005

?

↓

?

Ark International Training Seminars

INFLAMMATION

Overview of inflammation

Key toxins

Switch cytokine production to pro-inflammatory cytokine excess

IL-1, IL-6, TNFa INF- a, IFN- b

up-regulation of IL-12

stimulate production of IL-2 and IFN- 

prompt phagocytes to produce oxygen rich species and nitrogen rich species

initiates production of TNF-

a

April 2005

interferes with NADPH synthase and inhibits hexose monophosphate shunt Ark International Training Seminars

stimulates nitric oxide synthase and hence production of nitric oxide

Most common stimuli for cytokine expression
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Stress
• • • • • • • • •

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Low oestrogen

Psychological Allergies Chemical toxicity Toxic metal exposure Glycosylated protein Chronic subclinical infection Dysbiosis Radiation / electromagnetic Trauma
Ark International Training Seminars

April 2005

General activity of cytokines
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Cytokines involved in acute inflammation
• TNF-a, IL-1, IL-6, IL-8, IL-11 • And other chemokines, G-CSF, and GM-CSF

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Cytokines involved in chronic inflammation
• They can be subdivided into: 

Cytokines mediating humoral responses
• IL-4, IL-5, IL-6, IL-7, and IL-13

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Cytokines mediating cellular responses
• IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferon (IFN), transforming growth factor-ß (TGF), and tumour necrosis factor-a and ß (TNF).

April 2005

Ark International Training Seminars

Humeral versus cellular immunity
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Dominance of the humoral immunity
• Increased production of IL-4, IL-5, IL-6, IL-7, and IL-13 • Decreased production of IL-1, IL-2, IL-3, IL-4, IL-7, IL9, IL-10, IL-12, IFN, TGF-b, and TNF-a and ß.

• Check for parasites and mycobacterium.
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Dominance of cellular immunity
• Increased production of IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IFN, TGF-b, and TNF-a and ß. • Decreased production of IL-4, IL-5, IL-6, IL-7, and IL-13

• Check for viruses and bacteria.

April 2005

Ark International Training Seminars

Pro-inflammatory or activating cytokines
• TNF-a, • IL-1b, • IL-2, • IL-6, • IL-12, • IFN-a, • IFN-, • TGF.
April 2005
Ark International Training Seminars

Pro-inflammatory cytokines
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IL-1 comes mainly from macrophages and monocytes. IL-1 is induced by micro-organisms, microbial products, antigens, inflammatory agents, plant lectins, lymphokines and certain chemicals IL-1 activates the process known as the acute phase response.

• This response is characterised by production of a variety of hepatic proteins (e.g., C-reactive protein, serum amyloid A, fibrinogen, complement, alpha 1-antitrypsin)
Ark International Training Seminars

April 2005

IL-1
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activates adhesion molecules on vascular endothelium. (VCAM) stimulates the production of IL-8 that activates neutrophils. elicits the release of histamine from mast cells at the site of inflammation causing increased capillary permeability and vasodilatation. a potent mitogen for astroglial cells and induces astrocytes to synthesise NGF. interferes powerfully with the hypothalamic-hypophysealgonadal axis (HHGA).
• At the CNS level,
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decrease plasma LH levels (Luteinising hormone), a phenomenon attributed to the inhibition of hypothalamic secretion of LHRH and LHRH gene expression.

April 2005

Ark International Training Seminars

Effect of IL-1 & TNF-a on cartilage
adenosine

decreased plasma iron levels deposition of iron in synovial membranes

released by injured cells

with IL-1, inhibit erythrocyte production and produce anaemia not able to respond to iron supplementation

inhibit respiratory burst with high TNF- a high TNF- ais implicated in rheumatoid arthritis

Increased secretion of IL-1

Peroxynitrite and hypochlorite stimulates the production of proteases (collagenases, elastases)

H2O2 interferes with ATP synthesis (inhibition glyceraldehyde 3-phosphate dehydrogenase in chondrocyte)

April 2005

Ark cartilage degradation International Training Seminars

IL-2
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Generated by T lymphocytes after stimulation by antigen or mitogen Pro-inflammatory cytokine that plays a critical role in regulating both cellular and humoral chronic inflammatory responses. Largely responsible for immunologic memory.
• The immune system forms a long-term "memory" from antigen exposure so that any future contact will stimulate an immediate defence against that particular antigen.

April 2005

Ark International Training Seminars

IL-2
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Influence the maturation and differentiation of lymphocytes in the thymus and bone marrow. There are two major classes of lymphocytes:
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• B lymphocytes (B cells) derived from the bone marrow

• T-lymphocytes (T cells)

B cells express antibody molecules on their surface, and when stimulated by antigen, each B cell becomes a plasma cell that secretes antibodies specific for that antigen.

April 2005

Ark International Training Seminars

• T-lymphocytes (T cells) derived from bone marrow but matured by the thymus.
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IL-2

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T cells also express what appear to be antibody molecules on their surfaces, but unlike B cells, these molecules cannot be secreted T cells react to antigen stimulation by secreting other types of molecules;

• Thus, a foreign antigen stimulates both B cells and T cells, and the resulting immune response is specific for that antigen alone.

• cytotoxic ("killer") T cells secrete molecules that kill infected or abnormal cells on contact, • "helper" T cells secrete a variety of cytokines involved in the immune response.

April 2005

Ark International Training Seminars

IL-2
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After an antigen binds receptors on an individual T cell, the antigen stimulates the T cell to secrete IL-2 and to make IL-2 receptors. The T lymphocyte has two receptor sites;
• the first site readily binds IL-2, • the second site attaches more slowly to the IL-2 molecule.
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April 2005

It is the interaction at the second site, however, that activates the T cell, causing it to undergo complex changes in morphology, metabolism, expression of surface receptors, and the production of cytokines Seminars Ark International Training

IL-2
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Stimulates the proliferation of B cells, helping them to secrete antibodies IL-2 stimulates production of Natural Killer T cells
• They represent the first line of defence against intracellular pathogens because of their immediate responsiveness to IL-2. • In synergy with IL-1.

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Il-2 has been found to be low in persistent microbial infections and cancer and there is a considerable body of research into the immuno-stimulatory effect of IL-2.
Ark International Training Seminars

April 2005

IL-2
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↑ lymphokine secretion
• In turn ↑ IFN-, lymphotoxin, IL-4, IL-3, IL-5, GM-CSF {macrophage colony stimulating factor})

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Enhanced expression of MHC (Major Histocompatability Complex) class II proteins Stimulates fibroblasts to secrete extracellular matrix
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April 2005

NK cell

LAK cell

IFN-

IL-2 eosinophil IL-6 IL-10

Th1 cell IL-10 IL-6 Th2 cell IL-2 IL-5

Th2 cell IL-4 Th0 cell

IL-12

IFN-a

TGF

IL-6

Macrophage
April 2005
Ark International Training Seminars

IL-15

NO.

TNF-a

PGE2

IL-10

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April 2005

Derived from macrophages, fibroblasts, bone marrow, vascular endothelium and some T cells, from IL-1 stimulated B cells, antigens, mitogens and endotoxins. Major derivation is from visceral adipose tissue (produce 2-3 times IL6 than depot fat cells); adipocytes are also producing oestrogen in post menopausal women Inhibits the macrophage production of IL-1 (a feedback loop) and IFN-.
Ark International Training Seminars

IL-6

IL-6
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April 2005

Stimulates the production of immunoglobulin producing B cells Stimulates proliferation of thymic and peripheral T cells With IL-1, IL-6 induces T cell differentiation to “Killer” T lymphocytes Stimulates the liver to produce Acute Phase Proteins such as fibrinogen, serum amyloid protein A and a2macroglobulin.
Ark International Training Seminars

IL-6
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Activates Natural Killer cells (NK cells). Induces breakdown of the extracellular matrix Induction of osteoclastogenesis and osteoclast activity
• involved with cell signalling in bone turnover, which leads to increased conversion of osteoblasts to osteoclasts and the reabsorption of bone
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Wong PK et al. The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum. 2003;48(5):1177-1189.
Ark International Training Seminars

April 2005

IL-6
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It is upregulated in type 1 diabetes, infections, inflammatory thyroid disease, RA, systemic sclerosis, psoriasis and various cancers. Major functions in neoplastic processes.
• • • • Cell adhesion and motility Thrombopoiesis Tumour specific antigen expression Cancer cell proliferation.

• IL-6 may affect cancer progression by its actions on:-

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Depending on the cell type, IL-6 can either inhibit or stimulate cancer cell proliferation.

• Tumours stimulated by IL-6 include melanoma, renal cell carcinoma, prostate carcinoma, Kaposi's sarcoma, ovarian carcinoma, lymphoma and leukaemia, and multiple myeloma.

April 2005

Ark International Training Seminars

IL-6
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IL-6 levels are directly correlated with ageing in a variety of species, it may play an important role in the ageing process.
• Intriguingly, dietary restriction, the only experimental intervention that reproducibly prolongs maximum lifespan in mammals can restore a variety of physiologic parameters, including IL-6 secretion and serum levels to the level in youth. • DHEA, currently thought to influence various ageing processes also has been shown to diminish the age-associated rise in serum IL6.
Ark International Training Seminars

April 2005

IL-6
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an elevated IL-6 level is a strong and independent predictor of mortality for patients with acute coronary syndromes
• Vorchheimer DA, Fuster V. Inflammatory markers in coronary artery disease. JAMA. 2001;286(17):2154-2156.

April 2005

Ark International Training Seminars

IL-6 and hormonal function
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Glucocorticoids inhibit IL-6 expression.
• During times of stress or inflammation, IL-6 levels are increased. • IL-6 can then induce release of corticotrophin-releasing factor, which results in elevated systemic levels of corticosteroids. • This provides a mechanism for a negative-feedback loop.

April 2005

Ark International Training Seminars

IL-6
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Oestrogen inhibits IL-6 expression.
• Menopause or ovariectomy resulted in increased IL-6 serum levels and increased IL-6 secretion by mononuclear cells. • Studies have also demonstrated that oestradiol inhibits bone marrow stromal cell and osteoblastic cell production.

April 2005

Ark International Training Seminars

IL-6
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Important mediator of several infectious and autoimmune diseases. These include :• Rheumatoid arthritis • Inflammatory joint disease, particularly rheumatoid arthritis, which is associated with, increased synovial fluid levels of IL-6. • Sepsis • Human immunodeficiency virus (HIV infection) • Castleman's disease • Para-neoplastic symptoms associated with cardiac myxoma
Ark International Training Seminars

April 2005

Tc IL-2

MHC restricited cytotoxicity

TH1

IFN-b IL-1 LAK IFN-g Antigen Macrophage

non-spe cific cytotoxicity

ROS
Macrophages IL-1

NO

TH2

TNF
IL-4 IL-5

B lymphocytes

Antibody

April 2005

APC cell TH1 TH2 ROS NO TNF Tc LAK

Macrophage - antigen presenting T Helper cell 1 T Helper cell 2 reactive oxygen species nitric oxide Ark tumour necrosis factor cytotoxic cells Lymphokine-activated killer cell

International Training Seminars

IL-12
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Generated from T and B-lymphocytes, NK cells and macrophages. The production is of IL-12 is inhibited by IL-4 and IL-10.
• The stimulatory effect of IL-12 on TH1 development is antagonised by IL-4, a cytokine that promotes TH2 cell development.

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Proinflammatory cytokine. Excess production can indicate infection, inflammation, autoimmune disease and cancer Found to be elevated in autism and MS Enhances cytotoxic T cells
Ark International Training Seminars

April 2005

IL-13
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Enhances the expression of MHC class 11 proteins (Major Histocompatability Complex) and thus antigen production.
• MHC type 1 is always recognised by lymphocytes bearing cell surface protein CD8; MHC type 11 is always recognised by lymphocytes bearing CD4

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Increases CD23 expression. Causes the switching of antibody production to IgE and IgG4 Brain tumour lines over-express a receptor for IL13 and these receptors block IL-4, whereas normal cells share receptors between IL-4 and IL-13 Low in the synovium of RA patients
Ark International Training Seminars

April 2005

INTERFERONS
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Interferon is produced by T “helper” lymphocytes. There are two types of T cells:

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The helper T cells produce interferon and other cytokines in response to an antigen challenge. Before a B cell can produce and secrete antibodies, it must recognise a specific antigen and receive signals from certain cytokines.
Ark International Training Seminars

• Cytotoxic (or "killer") T cells, which aggressively screen other cells for signs of infection and malignancy and secrete toxic molecules to kill any aberrant cells; • "Helper" T cells, which cooperate with B cells (lymphocytes that mature in the bone marrow) in the antibody response to antigens such as bacterial toxins.

April 2005

INTERFERONS
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Functions:
• Interferons fight infectious disease. • They increase the phagocytic activity of macrophages. • Increase the cytotoxic activity of lymphocytes. • Inhibits the replication of intracellular pathogens.

April 2005

Ark International Training Seminars

IFN-a and IFN-b
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Both are generated by leukocytes and fibroblasts Their functions are :
• • • • Antiviral properties. Interferon activates phagocytes. Anti-proliferative properties. Interferon up-regulates MHC class I expression • Interferon a-2 has been used to treat chronic myelogenous leukaemia and other myeloprolific disorders, perhaps by inhibiting oncogene expression.
Ark International Training Seminars

April 2005

IFN-a and IFN-b
• Used in combination with retinoids, interferon a-2 has induced regression in advanced squamous carcinomas of the skin and cervix, suggesting that the cytokine may influence cell differentiation. • It also inhibits vascular and endothelial cell proliferation and thus has a place in treatment of melanomas, hypernephromas, and haemangiomas. • Because it can increase the intensity of antigen expression on certain tumours (ovarian and colorectal carcinomas), interferon a-2 has potential for diagnostics (imaging) and therapeutics (monoclonal antibodies).
Ark International Training Seminars

April 2005

IFN-
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IFN- is generated by T-lymphocytes and Natural Killer cells Its functions are: • Antiviral properties. • The development of TH1 from TH0 cells and the inhibition of TH2 cells. • It is the body’s most powerful macrophage-activating factor.
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over production of IFN- can be caused by toxins such as Epstein Barr virus
Ark International Training Seminars

• Increases the expression of both MHC type 1 and 11 proteins, thus enhancing antigen production. • Stimulates the expression of VCAM. • Stimulates the differentiation of cytotoxic T-cells. • Inhibits IL-4. • Promotes the synthesis of IgG2 by activated T cells

Mediator of oxidative stress, stimulating macrophages to produce free radicals (used to kill cancer cells) Induction of apoptosis

April 2005

IFN--inducing factor: (IGIF)
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It has been proposed that IGIF be designated as IL-18 Functions
• Induces IFN- production more potently than IL-12 • Induces the development of TH1 cells. • Enhances of NK cell cytotoxicity • Augments GM-CSF production • Decreases IL-10 production.

April 2005

Ark International Training Seminars

TNF-a
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Generated by macrophages, mast cells and T-lymphocytes. Macrophages are stimulated to produce TNF by IFN- (i.e. TNF-a is produced when IFN produces migration inhibition factor (MIF) when T -lymphocytes are stimulated by an endotoxin such as pathogenic bacteria or viral infections. TNF-awhen in high concentrations as when it is induced by an endotoxin, can have the following effects:

• Pyrogenic properties; either directly via stimulation of PGE2 synthesis by the vascular endothelium of the hypothalamus, or indirectly by inducing the release of IL-1. • The production of acute phase proteins. • The stimulation of the production of nitric oxide. • If TNF-a is produced for long periods, then it produces cachexia. • Destroys cells in the CNS that produce serotonin, leading to depression

April 2005

Ark International Training Seminars

TNF-a
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TNF-a and diet
• High levels of carbohydrates or fats increases activity of TNF • High levels of protein does not increase activity of TNF-a.

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TNF-a when produced in low concentrations:
• Up-regulates the inflammatory response. • Induces expression of ICAM-1, VCAM-1 and Eselectin. • Enhances killing of intracellular organisms such as Leishmania and Mycobacterium tuberculosis. • Activates leukocytes to produce IL-6 and TNF-a itself.

Levels are raised in vitamin B12 deficiency (with EGF) causing alteration Training Seminars Th2 balance in Th1 & April 2005 Ark International
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TNF-b
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TNF-b is produced by activated T-cells Its properties are similar to those of TNF-a and include:
• The induction of apoptosis (programmed cell death) in many types of transformed, virally infected, and tumour cells. • The stimulation of several PMN (polymorphonuclear leukocytes) effector functions. • TNF-b lyses tumour cells. • TNF-b activates neutrophils. • TNF-b increases the adhesion of leukocytes to the vascular endothelium.

Found in excess in MS, RA, infection and type 1 diabetes April 2005 Ark International Training Seminars
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Transforming growth factor-ß: (TGF-ß)
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Family of cytokines that includes five isoforms;
• TGF-ß1, ß2, and ß3 that are from separate genes yet, bind to the same high affinity receptor.

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 2005 April

TGFs are trophic polypeptides that stimulate the proliferation and differentiation of different cell types of mesenchymal origin Derived from T cells, platelets, and monocytes.: Inhibits T cell and NK cell proliferation and activation.
Ark International Training Seminars

Transforming growth factor-ß: (TGF-ß)
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At a site of injury,
• TGF-ß (stored in platelets) will be released upon the degranulation of mast cells. • TGF-ß then attracts monocytes and other leukocytes to the site, thus participating in the initial step of chronic inflammation. • TGF-ß then positively regulates its own production and the production and deposition of extracellular matrix components as well as the expression of integrins resulting in enhanced cell adhesion.

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Up-regulates IL-1, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and TNF-a.

April 2005

Ark International Training Seminars

Anti-inflammatory or suppressing cytokines
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IL-4, IL-5, IL-10, IL-13

April 2005

Ark International Training Seminars

IL-4
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Mainly derived from Th2 cells (CD4 cells), mast cells and basophils
• It is a structural homologue of IL-13

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Suppresses the production of pro-inflammatory cytokines
• • • • Suppresses the production of TNF-a, IL-1, IL-6 & IL-8 Involved in the development of Th2 subset Involved in B-lymphocyte production Initiates growth of mast cells

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Stimulates synthesis of extracellular matrix Cause the switching of antibody production to IgE and IgG
Ark International Training Seminars

April 2005

IL-4
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Responsible for the induction of CD8 Stimulates production of VCAM-1 Enhances expression of MHC class 11 proteins and thus antigen production Anti-inflammatory action in synovial membranes by inhibiting the proinflammatory cytokines IL-1, Il-6, IL-8 and TNF-a Its actions are antagonised by IFN- and vice versa. It is a synergist with IL-3 Low in the synovium of RA patients
Ark International Training Seminars

April 2005

IL-5
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Derived from Th2 cells (CD4 T helper cells) and activated mast cells like IL-4. Stimulates growth of eosinophils,
• which are responsible for killing the helminth family of parasites

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Stimulates the growth and differentiation of Bcells It induces the synthesis of IgA and IgM in mature B-lymphocytes Enhancement of T cell cytotoxicity High levels are associated with asthma and atopy
Ark International Training Seminars

April 2005

IL-5
 

Derived from Th2 cells (CD4 T helper cells) and activated mast cells like IL-4. Stimulates growth of eosinophils,
• which are responsible for killing the helminth family of parasites





 

Stimulates the growth and differentiation of Bcells It induces the synthesis of IgA and IgM in mature B-lymphocytes Enhancement of T cell cytotoxicity High levels are associated with asthma and atopy
Ark International Training Seminars

April 2005

IL-10




Generated from CD4 T cells, activated CD8+ T lymphocytes, B-lymphocytes, macrophages, activated mast cells and epidermal cells. It is an anti-inflammatory cytokine along with IL4 and IL-13.
• Down-regulates the macrophage production of IL-1, IFN- and TNF-a. • Inhibits the production of IL-2 induced IFN- by NK cells. • Promotes the inhibition of IL-4 and IFN- induced MHC class II expression on monocytes.



It is over-expressed in some viral, bacterial and parasitic infections
Ark International Training Seminars

April 2005

IL-10
  





April 2005

Inhibits nitric oxide production. Stimulates B-cell proliferation. Inhibits macrophage/monocyte activation. Suppresses activity of peripheral blood lymphocytes (important in graft rejection). High in the synovial fluid of RA patients, but not enough to suppress the pro-inflammatory response in RA
Ark International Training Seminars

Inducible cytokines


These cytokines have differing responses in different environments and influences

April 2005

Ark International Training Seminars

IL-3
 







April 2005

Generated from activated T-cells and mast cells. Stimulates eosinophils and B cell differentiation. Inhibits lymphokine-activated killer (LAK) cell activity. Shares several biological activities with GM-CSF. Supports the survival of cholinergic neurones. Stimulates production of proteoglycans
Ark International Training Seminars

IL-7







Derived from stromal cells in bone marrow and thymus. Stimulates proliferation of B-cell progenitors Stimulates mature T-cells Enhances cytotoxicity

April 2005

Ark International Training Seminars

IL-8




Derived from phagocytes, antigen-activated T cells, endothelial and epithelial cells, and even neutrophils. Controls cell migration to inflammatory sites





Stimulate granulocyte activity Up-regulates cell-surface adhesion molecule expression Hence enhancing neutrophil adherence to endothelial cells and facilitating their diapedesis through vessel walls.
• ↑ endothelial leukocyte adhesion molecule (ELAM-1) • ↑ intracellular adhesion molecule, ICAM-1

• By activating the chemotactic migration and activation of neutrophils and other cell types (such as monocytes, lymphocytes, basophils, and eosinophils) at sites of inflammation.



April 2005

Ark International Training Seminars

IL-9


 





Generated from CD4 T helper cells and some B lymphomas. Dependent on IL-4, IL-10 and IL-2. Promotes proliferation of T-cells – CH8 T cells. It inhibits lymphokine production by IFN-producing CD4+ T cells. Increase production of immunoglobulins and proliferation of mast cells.
Ark International Training Seminars

April 2005

IL-11
 

Generated from bone stromal cells and some fibroblasts. Functional homologue of IL-6 and can replace IL6 in the induction of acute phase proteins in the liver.
• Produces acute phase proteins in the liver. • Induces IL-6 expression by CD4+ T cells.

  



Promotes lymphopoiesis. Promotes the growth of haemopoietic cells. Stimulates T cell-dependent B cell immunoglobulin secretion, Stimulates platelet production.
Ark International Training Seminars

April 2005

IL-14







April 2005

Generated from T-lymphocyte and malignant B-lymphocytes. Induces proliferation of activated Bcells Inhibits immunoglobulin production It has been suggested that IL-14 plays an important role in an aggressive form of B-cell type nonHodgkin’s lymphoma
Ark International Training Seminars

IL-15
  

The human IL-15 gene has been mapped to chromosome 4, similarly to IL-2. Generated from epithelial cells, activated monocytes and fibroblasts. Shares many biologic properties with IL-2 and mediates its activity via a high affinity receptor comprised of a unique alpha chain (to IL-15) and the beta and gamma chains of the IL-2.

April 2005

Ark International Training Seminars

IL-15
    

Stimulates T-cell production by binding to IL-2 receptor sites Stimulates NK cell proliferation, as well as CTL and LAK activity. Enhances B cell expansion and immunoglobulin production. It functions also a T lymphocyte chemoattractant. IL-15 may be responsible for the recruitment and activation of T lymphocytes in the synovium of patients with rheumatoid arthritis where its levels have been found to be elevated
Ark International Training Seminars

April 2005

IL-16:








The only member of the "C" family of chemokines. It is an unusual cytokine in that preformed IL-16 is stored in CD8+ lymphocytes and is secreted upon stimulation with histamine or serotonin. It induces chemotaxis of CD4+ T lymphocytes. Initiates T cell mediated inflammation in asthma.
Ark International Training Seminars

April 2005

IL-17:


 



Generated from activated T lymphocytes. Stimulates IL-6 and IL-8 production . Enhances ICAM-1 expression Excess in synovium of RA patients.

April 2005

Ark International Training Seminars

Colony stimulating factors: (G-CSF and GM-CSF)


There are two forms of Colony Stimulating Factors:
• Granulocyte-Colony Stimulating Factor G-CSF). • Granulocyte macrophage-CSF (GM-CSF).



  

They are derived from monocytes, T lymphocytes, fibroblasts and endothelial cells that are activated by macrophage products such as the pro-inflammatory cytokines IL-1 and TNF. They both participate in acute inflammation. They both can stimulate neutrophils. GM-CSF can also activate effector functions of eosinophils and mononuclear phagocytes.
Ark International Training Seminars

April 2005

Epidermal growth factor
    

Trophic polypeptides that stimulates the proliferation and differentiation of different cell types. Potent stimulator of astrocyte proliferation. EGF is not synthesized by the developing neuronal cells, (but its homologue, TGF-a , is expressed in the brain.) During gliogenesis, EGF is detected in tissues and in the blood. EGF is known to strongly affect the morphology of astrocytes and induce upregulation of the glutamine.

• In the peripheral nervous system (PNS) studies have indicated that individual growth factors act as critical determinants of transmitter type. • In the brain, however, the initiation of neurotransmitter specific genes appears to involve more complex mechanisms, requiring the obligatory interaction of multiple signal molecules
Ark International Training Seminars

April 2005

Fibroblast growth factors (FGFs)




The family of fibroblast growth factors (FGFs) include several forms They occur in many peripheral tissues.
• The brain and pituitary are rich sources of FGF-b



They are potent mitogens for a large number of cell types..
Ark International Training Seminars

April 2005

GM-CSF & asthma


In asthma’s airway inflammation,

• GM-CSF, IL-3 and IL-5 perpetuate the eosinophil activation and their survival.  Probably derived from alveolar macrophages (2-3 times the level of control macrophages) or the T-lymphocytes present in the airways • IL-4 and IL-13 (stimulatory) and IFN- (inhibitory) control IgE synthesis • IL-1 and TNF-a up-regulation the expression of the endothelial adhesion molecule.

April 2005

Ark International Training Seminars

Hormone regulation


Hormone regulation:
• Upstream to the pituitary (stimulating hormones) and hypothalamus (regulating hormones • Downstream via metabolic pathways in relationship to the cofactors in their synthesis • Downstream via liver and other cellular detoxification pathways

April 2005

Ark International Training Seminars

Hormonal Immune reciprocity
 



 

The sympathetic nervous system (SNS) The parasympathetic nervous system (PNS) The hypothalamus-pituitary-adrenal cortex axis The hypothalamus – pituitary-thymus axis The hypothalamus-pituitary-thyroid axis

April 2005

Ark International Training Seminars

HPA axis (hypothalamic-pituitaryadrenal)


Adrenal – gonadal hormones
• Oestrogen 18- carbon chain • Androgens 19 carbon chain • Progesterone 21 carbon chain


The balance the glucocorticosteroid hormones (21 carbon chain) is important in regulating the inflammatory response

April 2005

Ark International Training Seminars

Female HPA axis
Higher Centres Hypothalamus

FEMALE HPA AXIS
Luteinizing Hormone-Releasing Hormone (LHRH)

Testosterone does not have a direct feedback to the pituitary
positive and negative Androgen feedback Luteinizing Hormone (LH) Follicular Stimulating Hormone (FSH)

aromatising hormone Oestradiol (O2) and oestrone (O1)
April 2005
Ark International Training Seminars

Male HPA axis
Higher Centres Hypothalamus

Luteinizing Hormone-Releasing Hormone (LHRH)

Direct negative feedback

Testosterone does have a direct feedback to the pituitary
Testosterone Luteinizing Hormone (LH) Follicular Stimulating Hormone (FSH)

Inhibin ? direct feedback

Oestradiol

April 2005

Ark International Training Seminars

Leydig cells

Sertoli cells

HPA axis


HPA axis (hypothalamic-pituitary-adrenal)
• Corticotrophin releasing hormone (CRH)
   

• ACTH
  

Anti-inflammatory The major stress response mediator of the CNS Immunosuppressive centrally under sympathetic stimulation Stimulated by oestrogen Responsible for cortisol production Anti-inflammatory Immunosuppressive

• Gonadal androgens

April 2005

• Hence capable of relieving symptoms of RA

Inhibit IL-6, TNF-a, IL-1 production
Ark International Training Seminars

HPA axis


HPA axis
• Melanocyte stimulating hormone (MSH)


Cytokine antagonist inhibiting:
• • • • IL-1 IL-6 TNF-a INF-

• TSH




Increases IL-2 ↑ immunoglobulin secretion by activating Bcells
Ark International Training Seminars

April 2005

HPA axis
• DHEA




Enhances IL-2 & INF- production Enhance Th1 response Enhance Th1 & Th2 activity Potent pro-inflammatory effects Prolactin levels correlate with the severity of the disease, not the number of swollen joints Lymphocyte derived prolactin may be the reason that cabergoline does not reduce CRP and ESRInternational Training Seminars Ark

• Oestrogens


• Prolactin
 



April 2005

HPA axis


Defective Neuroendocrine communication (NEI) characterised by abnormal response of cortisol, prolactin, vasopressin, and bendorphin to certain stimuli in RA.
• Adrenal and gonadal deficiencies thought to facilitate T cell dependent diseases (RA)- a predominantly pro-inflammatory terrain • Low testosterone & dihydrotestosterone, low DHEA • Excess prolactin exaggerates RA • These are not a response to inflammation but pre-exist the disease



April 2005

High oestrogen thought to facilitate B cell dependent immune complex diseases (Lupus)
Ark International Training Seminars

Effect of oestrogen on immune system
Cells
 

Thymocytes Lymphocytes
• • •

Physiological levels levels • ↑
• • • • • • • • ↑ ↑ ↑↑ ↑ ↑ ↑ ↑ ↑ ↑

Pharmacological
?

CD8 T-cells CD4 T-cells B-cells

↓↓
↓ ↑↑ ↓ ? ↓ ? ↓



Macrophages
• • •

Cytokine production Proto-oncogene production HLA expression



Endothelial cells
• •

Adhesion molecules Adhesion of peripheral mononuclear cells to endothelium



Cell apoptosis

• ↓

?

April 2005

Ark International Training Seminars

Effect of androgens on immune system
Cells  Thymocytes



Reduced synthesis of IL-2 ?↑ Inhibition synthesis IL-1 ? ↓ ↑ ↑ ?↑

Lymphocytes
• CD8 T-cells Cytokine production Proto-oncogene production HLA expression DNA synthesis Proteoglycan synthesis




Macrophages
• • •
  



Chondrocytes
• •
 



Cell apoptosis



April 2005

Ark International Training Seminars

Sex hormones and inflammatory process
Oestrogens physiological Androgens
stimulation inhibition inhibition stimulation inhibition

pharmacological

T-cell CD8 synovial membrane in RA
IL-1 IL-6 TNF-a IL-10

IL-2

B-cell CD5
INF-

April 2005

antigen: virus, bacteria, mycoplasma, parasites

antibodies (Including rheumatoid factor) Ark International Training Seminars

T-cell CD4

Low oestrogen and inflammation


Low oestrogen:
• Menopause • Surgery
 

Increase in pro-inflammatory cytokines Supplementation of oestradiol inhibits IL-1 and TNF-a and possibly inhibits IL-6



Cytokines modulated by oestrogen:
• IL-1, IL-6, TNF-a, M-CSF, GM-CSF, TGFb

April 2005

Ark International Training Seminars

Macrophage and T-cell pathways in RA
Th2 T-cells Stress low androgen conditions Ageing Macrophage Low DHEA IL-1 IL-6 TNF-a Th1 T-cells Low Testosterone
stimulation

IL-4, IL-5, IL-7, IL-10 Low DHEA

IL-2 INF-
inhibition

systemic IL-1 IL-6 TNF-a
April 2005
Ark International Training Seminars

systemic IL-2 INF-

Peptidergic nerve regulation


Pro-inflammatory
• Substance P


Potentiates angiogenesis

• Calcitonin gene related peptide


Anti-inflammatory
• Somatostatin

April 2005

Ark International Training Seminars

Hormones and immune system
Bone Neuropeptides marrow
ACTH Vasopressin CRH b-endorphin Enkephalin Insulin ↓ ↓ ↕ ↕ ↓ ↕ ↕ ↑

Thymus
↓

Antibody
↓

Cell mediated immunity
↓

Inflammation

↑ ↓ ↕ ↕ ↑

MSH
LH Somatostatin Substance P Vasoactive Intestinal peptide
April 2005

↓
↑ ↓ IgA ↕ ↓ IL-2 ↓ IL-4 ↕ IgA

↓

↓
↕ ↑

↕

Ark International Training Seminars

Hormone
ACTH CRH B-endorphin Encephalin FSH Growth hormone Insulin Luteinising hormone MSH

IL-1 ↕

TNF-a

IL-6

INF-

IL-2
↓

↑ ↑ ↑

↑
↕ ↓
↕

↕

↑

↑

↑
↑ ↑ ↑ ↑ ↑

↑
↑

↑
↓

↑
↓ ↓

Prolactin
Somatostatin Substance P

↑
↓

↑

↑

↑

↑

Thyrotropin releasing hormone
TSH
April 2005

↑
↓
Ark International Training Seminars

HPA : HPT axis
Hypothalamus- pituitary-adrenal axis Hypothalamus-pituitary-thyroid axis

hypothalamus hypothalamus CRH
inhibition

TRH pituitary TSH

zinc

SNS

pituitary

ACTH

ition inhib
glucocorticoids/ cortisol
inhi bitio n

bladde rwrack' iodine

thyroid
se le nium, v itamin D

adrenal cortex adrenal medulla

T4

deiodinase enzyme (liver & kidney)

Catecholamines/ adrenalin, noradrenalin, aldosterone

vitamin A, rosemary, zinc

+

T3

se le nium, zinc, v itamin E, ashwaganda

April 2005

increased mitochondrial function

Ark International Training Seminars

General pattern of stress response
 


     



Increased noradrenalin Increased dopamine Decreased serotonin Sympathetic dominance (adrenergic component). Loss of parasympathetic tone Decrease in hypothalamus-pituitary-adrenal cortex axis activity Decreased in hypothalamus-pituitary-thymus axis activity Decrease in secretion of growth hormone, prolactin and androgens Increase in ACTH, CRH, cortisol, oestrogens and somatostatin Increased Th2 immune activity

April 2005

Ark International Training Seminars

Hypoactivity of HPA axis
  



  

April 2005 

Fatigue Inflammation Autoimmune disease Myocardial infarction Apathy Anorexia Weight loss Insomnia

     

Weakness Loss of libido Pain Asthma Allergies Loss of mental concentration

Ark International Training Seminars

Hyperactivity of the HPA axis
    


 

Anxiety Agitation Insomnia Hypercholesterolaemia Increased triglycerides Fatigue Depression Hypertension

    



 

GI tract disorders Central obesity Loss of muscle tone Osteoporosis Loss immune function Poor recovery from illness or injury Infertility Reduced kidney function

April 2005

Ark International Training Seminars

food intolerance decreased production of digestive enzymes poor digestion increased gut permeability

genetic polymorphisms Stress in gut nutritional status toxins

Hepatic stress and altered liver detoxification toxic state toxins stress Produce systemic inflammation drug regeme infections food intolerance leaky gut and dysbiosis endogenous metabolites substance abuse: alcohol, tobacco, recreational drugs
April 2005
Ark International Toxins stored in adipose tissue Training Seminars

nutrient deficiencies

oxidative stress

mitochondrial damage

affecting: musculoskeletal system immune system endocrine system CNS CVS urinogenital system

Inflammation and the Gut


Gut bacteria (2½ to 3 pounds weight)





Any abnormal message is communicated from the gut bacteria to the receptor sites on the mucosal lining of the gut will modify the pro and anti-inflammatory balance. IL-10 decreased

• the second largest organ by mass in your body, second only to the muscles. • bacteria are connected to the rest of the body by the lymphatic system and the hepato-portal blood supply.



TNF a and IL-1b increased.

• IL-10 is an anti-inflammatory cytokine

• TNF-a and the IL-1b are proinflammatory cytokines.
Ark International Training Seminars

April 2005

CONTROLLED TURNOVER OF THE EXTRACELLULAR MATRIX


Cytokine and cell proliferation factor influence on matrix:
• IL-1, prostaglandin E2, PDGF, EGF all stimulate inflammation in low tissue pH (acidosis) and HA synthesis • Proteases break down the GAGs into HA fragments that bind too much water causing oedema and increased pressure • This is the case in acute inflammatory joint disease • This can be the result of trauma, abnormal usage or infection
Ark International Training Seminars

April 2005

AND THE EXTRACELLULAR MATRIX


PH



April 2005

In abnormal pH, (acidic environment) the matrix regulation is disturbed and fibroblast, macrophages and neutrophils will release proteolytic enzymes that breakdown the GAGs of the extracellular matrix. The fragments are then removed by macrophages.
Ark International Training Seminars

PH


AND THE MATRIX





This effects cellular metabolism by increasing the percentage of anaerobic respiration hence increasing the production of lactic acid and therefore further increasing the acidity. Since the extracellular matrix acts as a store of toxins, acidity prevents toxins from being removed into the matrix and hence preventing cell damage. The matrix stores toxins in an alkaline state and eliminates them in the acidic state.
Ark International Training Seminars

April 2005

PH


AND THE MATRIX

April 2005

This abnormal pH is evidence of a disruption in the gut where the normal fluctuation (circadian rhythm) of the extracellular matrix pH from acidic to alkaline state between meals has become defective, leaving a permanent acidic state. The acidity induces a loss of motion in the matrix as the proteoglycans become more rigid.
Ark International Training Seminars

OXIDATIVE STRESS AND THE MATRIX


In the presence of increased oxidative stress in the extracellular matrix, the free radicals can cause non-enzymatic breakdown of the GAGs. This can be a major factor in the developmental pathology of certain chronic conditions and cancer
Ark International Training Seminars

April 2005

STRESS RESPONSE AND THE MATRIX


Chronic inflammation induces a state where small short acting stimuli produce an exaggerated long term reaction in the matrix and even more structural changes and loss of regulation. These changes in the matrix are not just material, they modify the resonance and oscillation patterns of the tissues in question and contribute to their losing phase coherence with the rest of the body (cf encapsulation in Traditional Chinese Medicine).
Ark International Training Seminars

April 2005



Chronic disease In chronic disease, it becomes essential
to:
• treat the problem that is initiating the symptoms, • provide therapy to get back regulation capacity in the extracellular matrix  initiate Dynamic Stillness in the tissues  regulate matrix pH  restore mitochondrial function  clear toxic metal, chemical and other biological toxins  restore cytokine and other cell communication factor balance  improve life style diet and exercise • find the chronic hidden focuses of infection that are causing the dysregulation of the matrix.
Ark International Training Seminars

April 2005

Homeopathy: Inflammation


Neuroendocrine axis
• Ovarium compositum and Tonsilla compositum • Glandula suprarenalis suis-Injeel, Hypothalamus suis-Injeel and Funiculus umbilicalis suis-Injeel



CNS imbalance
• Thalamus compositum
 

Sleep disturbance Altered pain threshold
Ark International Training Seminars

April 2005

Homeopathy: Fibromyalgia


Connective tissue disorder
• Detox Homeopathics • Thyroidea compositum


Increase metabolism of the matrix Increase metabolism of the matrix Rebalance matrix pH and toxicity

• Pulsatilla compositum


• Ubichinon compositum


April 2005

Ark International Training Seminars

decreased production of digestive enzymes

etiology
Stress in gut genetic polymorphisms toxins

poor digestion increased gut permeability

nutritional status

Hepatic stress and altered liver detoxification

nutrient deficiencies

food intolerance

toxins toxic state Produce systemic inflammation stress drug regeme infections food intolerance leaky gut and dysbiosis endogenous metabolites substance abuse: alcohol tobacco recreational drugs

oxidative stress

mitochondrial damage

affecting: musculoskeletal system immune system endocrine system CNS CVS urinogenital system

April 2005

Ark International Training Seminars

Toxins stored in adipose tissue

Homeopathy: PATHOGENS


CELLULAR ECOLOGY.
• The primitive life of symbiotic organisms live in a strong alkaline pH, • bacterial life forms live in a mild alkaline pH, • fungal life forms live in a medium acidic pH • viral life forms live in a strong acidic pH.

April 2005

Ark International Training Seminars

Homeopathy: PATHOGENS




In order to keep the right environment, every microbe produces an organic acid: Mucor racemosus -- lactic acid, Aspergillus niger -- citric acid. These two primitive life forms that we all have, Mucor racemosus and aspergillus niger produce the lactic acid and citric acid respectively needed to maintain the “terrain” in a healthy alkaline form.
Ark International Training Seminars

April 2005

Further studies


Overview of homeopathic practice within a kinesiology framework:
• July 7th-9th RIBA, London • Key toxins • Pathogenic life forms • Balance of pH environment • Drainage remedies • Enderlein remedies

April 2005

Ark International Training Seminars

Further studies


Allergy and Toxicity Course:
• September 21st-24th RIBA, London • Detoxification • Key toxins; fungus, mycotoxins, bacteria, virus, toxic metals, radioactive metals, mycoplasma, chemicals • The gut • Mitochondrial function



Homeopathic and naturopathic approaches
Ark International Training Seminars

April 2005

Further studies


For further information:
• Email to Richard or Karen at arkintl@dircon.co.uk • Look on web www.arkinternational.co.uk • Ring 0207 833 3454 • Write to 144 Cloudesley Road, Islington, London N1 0EA

April 2005

Ark International Training Seminars

References


Matrix and matrix Regulation
• Pischinger; Haug ISBN 2-8043-4000-7



Homotoxicology and Ground Regulation System
• Hartmut Heine; Aurelia-Verlag ISBN 3-022907-69-5



Molecular Biology of the Cell
• Alberts et al; Garland Science; ISBN 0-8153-4072-9



Clinical Rheumatology: Neuroendocrine Immune Mechanisms of Rheumatic Diseases
• Chikanza; Balliere Tindall ISBN 0-7020-2182-2

April 2005

Ark International Training Seminars


				
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