IMMUNE CELL ROLE IN C.F.S.

I will here describe animal cells and proceed to describe immune cells.

In the non-medical communities, which I encounter, there is remarkably little understanding of the immune system.

For this reason, I am supplying much information to counter notions that the immune system is weak or not working!

Skin, intestinal and respiratory linings have physical barrier, secretory and chemical protective systems.

Since we have described prokaryotes we can specify that animal cells including human cells are eukaryotes (eu means "true").

They contain a nucleus, mitochondria, rough and smooth endoplasmic reticulum, Golgi complexes, lysosomes, peroxisomes and also ribosomes.

Cells start as stem cells and each line of cells proceeds to mature cell formation.

The following description provides basic understanding of a major arm of the immune system. (The cells and their products)

Specific immune cells exist for an array of functions. Signalling molecules and their receptors remain central to the orchestration of adequate immune protection.

Dendritic cells and macrophages, and Toll-like receptors (TLRs)

I will introduce these cells, which were first known to respond to microbial organisms

which enter them, by breaking them up, but are now known to have recognition receptors (Toll-like receptors), collectins and ficolins, activation chemicals (cytokines) and ability to make molecules, which present lymphocytes with processed antigens.

Collectin refers to collagen-like molecules with a lectin domain.

At this point I will elaborate recent research into Toll receptors, because this represents the conservation of an ancient life form defence against pathogens.

It is described as an “innate immune system”

“Toll” is the German word for ”weird”. A fruit fly, Drosophila, makes a protein which helps the embryonic form differentiate its top from its bottom.

Flies lacking the gene were weird looking.

In 1991, Nick Gay at University of Cambridge discovered that the inner part of the human interleukin-1 (IL-1) receptor resembled the sequences of this Toll protein.

Hoffmann and colleagues at Strasbourg showed that Drosophila used the toll protein to defend against fungal attack.

In due course it has been found that flies, starfish, water fleas, nematodes and plants all have many Toll-like receptors (TLRs).

These receptors have been specified and human beings have at least 10 TLRs.

TLRs are also responsible for the induction of dendritic cell maturation, which is responsible and necessary for initiation of adaptive immune responses.

Each one is involved in recognition of specific microbial chemicals.

They seem to work in pairs. One part of the TLR molecule protrudes from the outside of the cell membrane, and each inner part gives rise to specific molecular sequences inside the cell.

Different cells have different combinations of these TLRs.

A TLR1 in combination with TLR2 binds to uniquely bacterial lipopeptides (lipid-protein combinations) and to molecules called GPI-anchored proteins in parasites.

A TLR2 paired with TLR6 binds to lipo-techoic acid in gram-positive bacteria, and zymosan in fungi.

TLR3 recognizes genetic material from viruses.

Two TLR4s paired bind to lipopolysaccharide from gram-negative bacteria.

A TLR5 binds to flagellin in the tails of motile bacteria.

TLR9 recognizes a signature genetic sequence called CpG in both bacteria and viruses, (distinct from mammalian CpG sequences.)

It appears that it is difficult for pathogenic organisms to avoid these TLRs.

The functions of TLR10 and the partners of TLR3, 5, 7,8 and 9 are presently unknown.

Once the microbial chemical triggers the receptor, the cell makes specific cytokines, which signal other consequences, including recruiting other cell responses and gene activations.

The specific responses by the lymphocytes are described in the next section.

All the TLRs perhaps excepting TLR3 hand the signal to an adapter protein called MyD88.

TLR2 and 4 are helped to signal via a protein called Mal.

TLR3 relies upon a protein called Trif, and TLR4 also requires Trif and Tram proteins.

TLR3 and 7 which recognize viruses produce sequences leading to release of interferons.(antiviral cytokines) (e.g. TLR3 binds to double-stranded RNA like West Nile virus, while TLR7 binds to single stranded RNA such as HIV)

TLR8 binds to single-stranded viral DNA.

TLR2 activated by bacteria, results in release of different cytokines.

People with an underactive form of TLR4 are 5 times as susceptible to bacterial infections.

People with defective TLR5 due to a mutation are much more susceptible to Legionnaires disease.

Overactive TLR4 seems to lead to autoimmune diseases.

In systemic lupus erythematosus, TLR9 reacts to the body’s own DNA.

There is considerable potential to deal with diseases by altering TLR responses.

TLR activators:

TLR4 activator. (MPL for allergy treatment and vaccine adjuvant)

TLR7 activator. ANA245 (isatoribine) is being trialled for hepatitis C.

TLR7&8 activator. Imiquimod is antiviral for viral warts and reverses basal cell carcinoma.

TLR9 activator. Promune is a vaccine adjuvant and is used in treatment of melanoma and non-Hodgkins lymphoma.

TLR inhibitors:

TLR4 inhibitor. E5564 anti-sepsis trials.

General TLR inhibitor.

(1) RDP58 for ulcerative colitis and Crohn’s disease.

(2) OPN201 for auto-immune disorders.

These therapies are likely to need a good deal, of care and understanding of pros and cons.

Laboratory identification of vulnerable people at several levels (e.g. HLA haplotypes and Toll receptor status) could be very productive of better therapies.

Mannose binding lectin

I turn to mannose binding lectin, which came to light with an infant who was prone to bacterial infections, and was found to be deficient in a factor required for pathogen opsonisation.

Mannose binding lectin (MBL) activates complement in an antibody independent fashion.

There are several common inherited polymorphisms in the MBL gene, and the clinical patterns seem to be of susceptibility to infection and autoimmune disorders.

This activation is triggered when macrophages detect certain organisms, and in response secrete interleukin-6 which is carried in the blood to the liver, evoking release of the MBL, an acute phase protein

The gene which codes for it is called MBL2, and is located on chromosome 10.

The missence mutations have now been documented, and are common.

I mention the amazing significance of certain peptide dimers. trimers and oligomers.

In this case, a trimeric configuration allows each peptide to perform certain functions.

Each peptide has a C terminal calcium-dependent lectin domain, which recognizes repetitive oligosaccharide moieties on a wide array of pathogens.

Functional MBL circulates as oligomers, allowing interaction with the microbial saccharides to give rise to conformational changes in the MBL and activation of mannose associated serine proteases (MASP)

This function is quite similar to initiation of the classical complement pathway C1q.

As mentioned mutations are common and either homozygosity or compound heterozygosity can give low serum levels of MBL.

The reasons for the high prevalence are so far not clear, and studies are underway to clarify susceptibility to meningococci, streptococci and staphylococci.

Vulnerability to HIV and probably Hepatitis B appears to be increased with MBL deficiency.

MBL recognizes mannan in fungal cell walls and again deficiency seems to make subjects more susceptible to fungi.

Recombinant MRB has been produced, but studies are at an early stage.

I will elaborate other functions of dendritic cells and macrophages later.

 

Lymphocytes

Immune cells are divided into thymus-derived cells (T lymphocytes) and bursa-derived (B lymphocytes) which respectively are involved in cell mediated and humoral (antibody) mediated immunity.

The body is patrolled by billions of T cells of which the majority appear to be dormant.

T cells must not launch attacks on the host's own cells.

In the development of T cells, mechanisms are set up that ensure that this does not happen. In some diseases there is a breakdown in these mechanisms.
ANTIGEN RECOGNITION AND T CELL ACTIVATION.
Antigens are generally peptide sequences, polysaccharides or nucleotides from outside the body (non-self)

T cells require 2 signals for activation.

(1) Signal 1 is antigen-receptor ligation.

(2) Signal 2 for B cells and cytotoxic T cells is delivered by helper T cells, and for helper T cells is delivered by the antigen presenting cell.

 

ANTIGEN-PRESENTING CELLS

T cells recognize antigens only on the surfaces of antigen-presenting cells (APCs).

Macrophages and dendritic cells.

These are the antigen processing and presenting cells. (Ephraim Fuchs1997)

The ligand for the T cell receptor is generated by the APC through processing and presentation of the antigen.

Foreign proteins in intracellular compartments are degraded into peptide fragments and these peptides then associate with the specialized antigen-presenting molecules encoded by the highly polymorphic genes of the MHC.

The MHC-peptide complex is exported to the cell surface, and the T cell receptor.is then ligated by a complex determinant.

Macrophages are thus crucial cells for the processing and presentation of antigens.

Some intracellular pathogens have the capacity to delay or prevent maturation of phagosomes in the macrophage.

Work by deCC, Thilo L in Paris showed that after infection of macrophages with mycobacterium avium, phagosomes became depleted in membrane components and through interchange of constituents, early endosomes also became depleted.

Ordinarily the phagosomes are microbicidal organelles

Numerous pathogens such as Toxoplasma gondii, Coxiella burnetii, Leishmania, mycobacteria, salmonella, and Legionella species can thrive in macrophages, evading lysosomal degradation and even multiplying. (Amor and Swanson)

 

Dendritic cells

These cells have long arms or dendrites and are found in many sites including skin (here they are called Langerhans cells) and mucous membranes.

They have stem cell precursors in the monocyte line, as do macrophages.

Some capture invading microorganisms, engulfing them in vacuoles.

They are highly efficient in capturing and presenting antigens, and activate T helper cells and T cytotoxic cells.

Researchers are interested in the role of particular subsets of these cells in setting the type 1 and 2 (TH1 and TH2) T cell responses as described below.

Some dendritic cells can produce interferon a.

A subset of dendritic cells make DC-SIGN, a molecule which can bind to the outer coat of the human immunodeficiency virus.

Other infectious agents can alter dendritic cell responses.

Malarial parasites bind to dendritic cells and prevent them from maturing.

Some of the herpes virus family such as cytomegalovirus also interfere at this level.

 

MHC MOLECULES

MHC class 1 molecules are expressed on the surfaces of almost all nucleated cells, and present peptides consisting of mainly 8-11 amino acids. The MHC-peptide complex is formed in the endoplasmic reticulum and is brought to the cell surface for recognition by CD8+ T cells.

MHC class 2 molecules present mainly 12 -24 amino acid length fragments that have been taken in from outside the cell. The class 2 proteins are expressed on the surface of a limited number of cell types, thymic epithelium, B lymphocytes, activated macrophages and dendritic cells.

The peptides are generated in and associate with class 2 molecules in endocytic vesicles and are brought to the surface for recognition by CD4 + T cells.

TH1 and TH2 setting.

During the description of T cell transformations researchers describe T helper cells being set into TH1 or TH2 states.

This setting of T cells into the TH1 or TH2 states may turn out to be extremely important.

T helper cells termed TH1 cells appear to be involved in getting T cells to attack intracellular organisms, but are also involved in diseases such as multiple sclerosis and juvenile onset diabetes, whereas T helper cells being set in TH2 forms appear to be involved in antibody production and in allergy.

In autoimmune diseases not only are there genetic markers, which influence the kind of immune response, but also there appear to be factors evoking greater dendritic cell activity and a higher tendency to ingest DNA and result in varieties of anti nuclear antibodies. One such stimulus is increased production of interferon alpha

There are specific cytokines associated with these cells.

TH1 cells produce interleukin2 (IL2), IL6, tumour necrosis factor alpha (TNFa), and interferon gamma (IFg).

TH2 cells produce interleukin4 (IL4), interleukin 10(IL10), and probably interleukin5 (IL5).

If a dendritic cell provokes the wrong kind of response in T cell and cytokine profile, the outcome can be persistent disease.

With leprosy, a type 1 response leads to a mild tuberculoid form of the disease, but a TH2 response gives the more serious lepromatous disease.

Specific ratios of TH1/TH2 cells occur and the above associated cytokines are released. This TH1/TH2 description is probably over-simplified.

In clinical practice we need to be able to assess T cell activity and cytokine production, but at present it is not a routine form of testing.

We need to consider the likelihood that infectious viruses and bacteria have evolved defence molecules that divert the immune system, thus enabling them to keep a pathological process going.

As well dendritic cells can be harvested from cancer patients and grown in a laboratory with tumour cell antigens. Reinjected with their processed antigen, they evoke enhanced immunological activity against the cancers (particularly melanoma)

Cytokines that activate dendritic cells also may have a place in the future.

To summarize the above, a crucial requirement is for immune cells to recognize and read specific antigens from microorganisms and other foreign materials. This recognition involves macrophages producing an antigen presenting protein, which attaches to some peptide groups on the antigen and allows T cell receptors that are specific to other groups on the antigen to allow specific clones of T cells to be activated. As well the macrophage phagosomes are important in the lysis of microbes inside the cell.

Activated T cells can be characterized by laboratory measurement of surface markers.

Glycoproteins are a crucial component of the recognition mechanism. The arrangements of these glycoproteins give the specificity of the surface markers. CD means "cluster determinant" and from here on we can explain specificities of cells by their CD classification.

T helper and T cytotoxic cells.

T cells can be divided into T helper cells (CD4 cells), and cytotoxic T cells (some of these have CD8 surface markers.)

Cytotoxic T cells tend to shift into a TH1 state and are concerned with dealing with intracellular infections.

T suppressor cells

There are also T suppressor cells, with capacity to decrease the risk of immune reactions towards self. Sakaguchi at Kyoto university in Osaka found T cells with CD4 markers which also possessed CD25 molecules.

These cells can decrease activity of killer T cells possibly by their responses to TGFb and IL10.

T suppressor cells have a surface receptor called glucocorticoid-induced TNF receptor(GITR.)

Blocking this receptor has evoked tumour reduction in mice.

Vitamin D deficiency may result in poorer T suppressor cell function in auto-immune diseases. D deficiency worsens the outlook in tuberculosis.

In some circumstances the activity of these suppressor cells may decrease the effectiveness of other T cells against intracellular infections and also malignant cells.

In mouse experiments antibodies that blocked TGFb and IL10 blocked tumour s/leukaemia induced by Friend leukaemia virus, and reduced CD25 cells.

(Also CD8 cells.)

T natural killer cells

Natural killer (NK) cells are large granular lymphocytes, which kill target cells that express little or no HLA class1 molecules.

Such target cells are virally affected cells and malignant cells. NK cells express receptors that inhibit killer cell function when self-MHC class1 is present.

Darryl See cites the T (NK) cells as improving in function, when CFS sufferers consume glyconutrient supplements.

I have not found other literature to support this claim.

We can now link immune cell abnormalities, viral/cell interaction and cytokine release with the metabolic abnormalities in C.F.S.

 

VIRAL PERSISTENCE AND SUBVERSION OF IMMUNE CELL MECHANISMS.

Dr Darryl See, trained in microbiology and immunology and working at the University of California at Irvine, has identified high loads of HHV6, and impaired NK cell (cytotoxic T cell) function in C.F.S. Once more there is a need for someone to validate this claim.

Konnie Knox and Donald Carrigan in Milwaukee also report identifying HHV6 in CFS patients.

HHV6 has genes which modulate the immune system and it is estimated that up to 1/3 of the genome of some herpes viruses could be devoted to this kind of avoidance or subversion of immune mechanisms.

The prevalence of these infections in adults is unclear, and most laboratories only check serology for HHV6.

More on CMV

Cytomegaloviruses continue to attract a large amount of research.

How do they evade immune defences?

Interference with antigen presentation

Expression of the HCMV matrix protein pp65 (UL83) results in several phosphorylated proteins or peptides. Phosphorylated threonine residues within immediate-early proteins may severely restrict access of the proteins to proteasomal degradation or divert it to a different pathway. (Gilbert et al 1993,1996)(Schmolke et al 1995)

Peptides pass the membrane of the endoplasmic reticulum (ER) through translocation by the transporter associated with antigen presentation (TAP) for assembly into ternary MHC class1 complexes.

Expression of the HCMV-encoded unique short 6 (US6) gene product results in inhibition of TAP, and peptide translocation is thereby inhibited.

Some other herpes viruses are also able to block TAP.

HCMV expression of US3 protein also impairs maturation and intracellular transport of MHC class 1 heavy chains, which gets trapped in the ER instead of proceeding to the cell surface.

HCMV gene products US2 and 11 result in degradation of MHC class 1 molecules.

Down regulation of MHC class 2 expression or function

HCMV and MCMV are able to interfere with CD4+ T -cell recognition of infected cells by inhibition of MHC class 2 peptide presentation on endothelial and epithelial cells.

When this happens in CMV infected macrophages, the CD4+ T cells appear to be unable to recognize those macrophages

Early CD4+T-cell activity influences CD8+ T-cell activity which is crucial for control of viral diseases.

Interference with NK cell mediated killing

HCMV and MCMV can induce a functional paralysis of dendritic cells.

NK cells express both activating and inhibitory surface receptors.

HCMV express MHC homologues that engage killer cell inhibitory receptors (KIRs) and function as viral decoys to prevent NK cytotoxicity.

(E.g. HCMV encodes gpUL18 ,an extensively glycated type 1 TM protein which has an amino acid identity sequence of approximately 21% with human polymorphic MHC class molecules.

Mutated cytomegaloviruses and the simian CMV are strong candidates for a similar role in CFS and related illnesses.

This work has been developed by Dr W John Martin in Rosemead, California.

Martin claims his data includes cytopathic effects produced by CFS patient's serum of cells in vitro, and also extensive polymerase chain reactions (PCRs) on the viral material.

He has further identified a simian (green monkey) CMV in some of his CFS patients. (See later)

The problem is that no one else seems to have replicated this work.

It would be difficult to suppose that other herpes viruses do not have similar actions.

Dorries cites examples of viruses escaping T cell-mediated eradication by various means, including interference with the MHC class1 presentation pathway of the host cell, or hiding in cells which lack MHC class 1 expression.

This may result in life-long persistence of the virus in some locations, such as the brain.

 

GENETICS AND T CELLS.

One genetic element is the encoding of "recognition" molecules by specific HLA complex genes.

By analogy, in rheumatoid arthritis, HLA-DR4 determined by a specific gene is involved in binding of foreign peptides and facilitating their presentation to specific T lymphocytes.

Closer examination revealed that the class II DR markers for rheumatoid arthritis (DRb*0401 and DRb*0404 have a similar sequence of amino acids in the third hypervariable region of the b chain.

It seems likely that there are polygenic determinants of many common diseases interplaying with environmental influences and pathogen exposures. (E g Type 1 diabetes)

It may emerge that one such interplay can occur through lectins in common foods such as grains, when peptide sequences in these proteins are not broken down enough. (Cordain)

Lectins are relatively resistance to digestion.

Amino acid sequences which are like those of antigens, may evoke immune cell recognition, and undesirable consequences.

A glycine-rich cell wall protein (GRP) in cereals and legumes has a 15 amino acid sequence in common with collagen, procollagen, and E B virus nuclear antigen 1, and can stimulate T lymphocytes.

This may mean that we need to think beyond gluten in terms of wheat intolerance.

Recently a CMV peptide sequence has been associated with auto-immune disorders.

The situation of pregnancy allows male or female cells from the foetus to enter the mother's body, and this may be yet another factor which gives rise to a higher prevalence of auto-immune diseases in females.

As well with seeds and cereals, lectin binding to glycans on brush borders of cells may lead to damage to villi and change gut wall permeability to lectins and other substances.

Such phenomena may be important in inflammatory bowel disease and rheumatoid arthritis, but also in CFS sufferers.

Some dairy product proteins are also suspect in CFS. (E.g.Analogy being A1 beta casein increasing risk of in type I diabetes)

This claims is still being disputed!

 

B CELLS AND ANTIBODIES.

The other crucial lymphocytes are called B cells. These make specific antibodies in response to reading virus particles. T helper cells can signal these cells to become active in the humoural part of immune defence.

This is a crucial aspect of how the body deals with extracellular infectious organisms.

Antibodies are immunoglobulins. The binding of antibodies to virus enables destruction of viruses to occur.

The receptors on B cell surfaces bind portions of whole molecules in their native or denatured conformation.

The portion of the molecule that is bound by antibody is called the determinant or epitope.

A fascinating rearrangement of the hypervariable region of the immunoglobulin molecule enables the antibody to be highly specific in it's binding to the antigen.

 

CELL SIGNALLING - CYTOKINES AND INTERLEUKINS

Literally meaning "cell activating" or regulating, cytokines are soluble proteins produced by a variety of cells, involving signalling to other cells, in regulation of growth, development and activation of these other cells. In the immune system this is a crucial part of the function of the system, as well as mediating the inflammatory response.

Many cytokines are capable of acting on many different cell types.

There appear to be different cell types of receptors for the same cytokine.

Categorization of cytokines is difficult because of over-lapping functions.

In general cytokines influence gene activation, which results in cellular activation (often specific protein activation), cell growth, differentiation, functional cell surface molecule expression and cellular effector functions.

The cytokine milieu can influence whether we make a cytotoxic or antibody response to a particular antigen.

Some chemical messengers/lytic proteins seem to be slightly different from these cytokines.

These include perforin and granzymes.

These are known to play a role in some situations of apoptosis.

Cytotoxic T lymphocytes mediate lysis of target cells by various mechanisms, including exocytosis of lytic proteins (perforin, granzymes) and receptor-ligand binding of Fas/APO molecules.

Death of target cells is characterized by either necrosis or apoptosis, depending on the killing mechanism used and on the metabolism of the target cell itself.

We return to the subject of receptors.

 

CYTOKINE RECEPTORS

The receptor is a specific structure located on the cell membrane. It is made of glycoprotein.

These are grouped into 5 families.

Specific cytokine receptors are responsible for ligand specific binding.

a) Ig superfamily (IL1)

b) Cytokine/haematopoietic growth factor (Type 1) receptor family (IL6, IL2, IL4)

c) IFN (type II) receptor family (IFN alpha)

d) TNF (type III) receptor family (TNF)

e) Seven transmembrane helix family (chemokines) (B adrenergic receptors)(Harrison's textbook of Medicine)

A whole cascade of signalling ensues in the course of, for example, an inflammatory illness.

G protein-coupled receptors (GPCRs) initiate diverse down-stream signaling events in response to ligand stimulation, as rapid activation of the extracellular signal-regulated kinase ERK1 and ERK2.

Monocyte chemotactic protein-1 (MCP-1) binds its G-protein-coupled seven transmembrane (TM) receptor, CCR2B, and causes infiltration of monocytes/macrophages into areas of injury, infection or inflammation.

This is very significant in TH1 type diseases.

Cytokines and chemokines have been implicated in the pathogenesis of Type 1 diabetes mellitus (T1DM) and its microvascular complications. Recently, genetic variants of monocyte chemotactic protein-1 (MCP-1), CC-chemokine receptor 2 (CCR2), CC-chemokine receptor 5 (CCR5) genes have been identified.

The following section on interleukins is merely to illustrate some details of what may happen when particular cytokines interplay with their targets.

 

INTERFERONS

Chemicals called interferons, which can be produced by all human cells, induce at least 3 types of antiviral effects.

 

(1) Induction of 2'-5' oligo A synthetases (synthases) (requires double stranded RNA for activation). When activated, the synthase polymerizes oligo A and activates RNAse L, which degrades single strand RNA of viruses.

Increased levels of 2'-5' oligo A synthase has been identified in one study of chronic fatigue syndrome.

Increased RNAse L of a particular molecular size seems to be a marker of interferon activity.

Normal RNAse L is an 83kDa polypeptide.

Suhadolnik and colleagues found that mononuclear cells in the blood of chronic fatigue sufferers had a 37 kDa form of RNAse L not found in controls and Mordechai found that chronic fatigue syndrome sufferers had a deficiency in an inhibitor of RNAse L.

De MeirLeir, Bisbal and colleagues found decreased levels of both normal 83kDa RNAse L and increased levels of37kDa RNAse L in CFS sufferers.

The ratio of the 37 kDa to 83 kDa forms was high in 90% of the CFS patients compared with 1% of normal subjects, and none of the depressed and fibromyalgia control patients

They note (in 2001) that type 1 interferons elicit apoptotic responses in targeted cells by inducing the expression of 2,5 oligo A synthetase, RNAse L and the p68 RNA dependent kinase (PKR)

Cell produced or pathogen produced elastases may cleave the large form ,producing the small form.

(2) Activated PKR induces apoptosis by translation (through eIF2 phosphorylation) Induction of PKR (a serine and threonine kinase which is also activated by double strand RNA).

The PKR phosphorylates and negatively regulates the translational initiation factor e IF 2 alpha shutting down protein synthesis in the infected cell, and by a mechanism involving activation of caspase 8 mediated by the fas associated death domain.

When an infected cell is injured it may be better for it to self-destruct (apoptosis).

(3) Induction of Mx proteins, a family of GTPases that inhibit replication of influenza virus.

Other cytokines almost certainly play a part in chronic fatigue. Many cell types in acute phase response make IL1. IL2 is involved in T cell activation.

I have mentioned the specific TH1 and TH2 cytokines

Activated macrophages can produce TNFa

TNFa and b are small non-glycosylated proteins.

IL6, TNF alpha and Interferon gamma appear to have important roles in inflammation, fever and other cell activations.

They also down regulate the PPAR gene and products.

Polymorphisms of the genes for these cytokines and IL10 may increase the risk of certain disease manifestations.(and decrease the risk of other diseases.)

Interleukins act on the previously mentioned specific interleukin receptors in cells .

In these ways specific T cells can signal other cells such as macrophages and B cells (which make antibodies) to shape activity in those cells.

In diseases, the interleukins, or perhaps their receptors, may also be subject to pathological processes.

It is anecdotal but many people with chronic fatigue seem to have been through a high level of stress prior to the onset of the condition.

Of interest is the report that in influenza underlying stress increased the production levels of interleukin 6.

Several intracellular pathogens evoke increased levels of IL10, which can inhibit the capacity of monocytes and macrophages to induce T cell activation.

IL10 is a very important cytokine with strong immunosuppressive and antiinflammatory activities.

It is a cofactor for growth and differentiation of B cells, mast cells, and some T cells.

It is secreted by activated T cells, B cells and monocytes and binds to its specific receptor on all haemopoietic cells.

It inhibits T cell production of IL2.

A homologue of IL10 was found in the genome of HCMV, and this inhibits a number of immune functions.

There are circumstances where particular interleukins play a helpful role in body maintenance in the face of pathogen attack and chemical injury and the specific sites of interleukin release and the balance between interleukins significantly shapes disease processes.

Many studies have shown some increase in particular interleukins in chronic fatigue syndromes but there is not enough consistency to be sure as to whether high or low levels of particular interleukins correlate with the syndrome.

 

HEAT SHOCK PROTEINS (HSPs)

For about 50 years, there has been awareness of cell products of heat exposed organisms (initially fruit flies).

It is now clear that these ubiquitous molecules have many roles in evolution, in influencing individual cells, and in defences against cancer and pathogens.

They are also called” chaperones” in that they have roles in inhibiting undesirable interactions and in promoting desirable ones.

HSPs tend to associate with a wide range of client proteins (not like the specificity of ligands with receptors.)

In particular they are associated with specific protein folding,dismantling of damaged proteins, and escorting them away from unwanted locations.

Proteins are assembled in ribosomes from DNA transriptions on to messenger RNA.

They need to be delivered to particular sites at particular times., and with a correct shape.

There are a number of properties of amino acids(AAs) which enable them to connect.

Hydrophobic amino acids nestle inside protein structures (away from water), while hydrophilic amino acids tend to face outwards.

The HSP 60 is cage like and helps by having an inner hydrophobic site for hydrophobic AAs, and the protein shape folds to optimise its shape.

Scientist coin names fro these HSPs (foldases)

HSP70 by contrast is an” unfoldase!”

Many HSPs are not like cages, but grab AA sequences by their “elbows”

 

ALLERGY

There have been a number of reports on higher prevalence of some allergic states in chronic fatigue syndromes. Cytokines released in allergy play significant roles in the genesis of some of the clinical features.

It is interesting to ask about what it is that diverts some T cells to the TH2 path, or what prevents such a diversion.

Certain pathogens probably possess genes that can activate a diversion of host responses into particular patterns.

Inhaled allergens can increase intercellular adhesion molecule (ICAM1) receptor expression on respiratory epithelium and this receptor is used by rhinoviruses to gain entry into mucosal cells.

This opens up therapies which down regulate ICAM1 receptors in allergic diseases (e.g. antihistamines and corticosteroids)

I hope that this chapter will help the reader to avoid using terms like “weak immune system”, and appreciate the complexity and elegance of this biological system.

 

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