This chronic multisystem disorder has defied full understanding, but intriguing clues are emerging.

 

Clinical features vary a good deal, but perhaps 10% have no symptoms and are discovered through chest X rays.

 

About 90% have abnormal chest Xrays, and more than 75% have enlarged intra-thoracic lymph nodes.

 

80% are significantly fatigued.

 

Fatigue, malaise, fever, anorexia, weight loss, and some respiratory symptoms or mild joint aching are possible.

 

The liver is involved in >60% of cases.

 

Joint pain and radiological changes around joints can occur in 25-50% of cases.

 

Skin lesions (one subgroup may get erythema nodosum.) are seen in about 20% (more in European patients).

 

 Eyes are involved in about 25%, and 5 % have neurological features.

 

The spleen is involved in many cases without clinical splenomegaly, but 5-10% may have a palpable spleen.

 

About 5% may have heart involvement.

 

The granulomata contain mononuclear inflammatory cells, mainly CD4+ TH1 lymphocytes and macrophages (mononuclear phagocytes.)

 

Exaggerated T helper CD4+ lymphocyte (TH1 setting) responses seem to be involved with the possibility that there is a cellular immune response to both antigens from outside and perhaps self-antigens.  That there is an inherited element is suggested by the remarkable variety of prevalence among certain ethnic and racial groups and where it is more common in monozygotic than dizygotic twins.

 

 The Major Histocompatibility Complex (MHC), has genes on human chromosome 6p21, and is a principal susceptibility locus for many human autoimmune diseases. Susceptibility to a number of these diseases, including rheumatoid arthritis (RA), multiple sclerosis (MS) and type 1 diabetes, is associated with particular alleles of HLA-DR and/or -DQ genes, providing strong evidence for a significant role of MHC class II restricted antigen presentation in these disease processes. In several DR-associated autoimmune diseases it has been possible to define structural features of the relevant MHC class II molecules that determine their interaction with peptides.

HLA haplotypes DRB1* 1501, *0101 and DQB1 *0602 appear to be overrepresented in sarcoid cases.

Chemokine gene (e.g.CCR) and even ACE polymorphisms have been shown to play some part.

 

It appears that the TH1 setting does not shut down in sarcoidosis, but this raises the question as to what drives it?

 

Another aspect of the pathology is the probability that interleukins attract and activate macrophages and similar cells and that something stops the suppressor side of the immune response from being shut down. 

 

Proteins which recruit macrophages from monocytic stem cells are probably important, and one known recruiting substance is monocyte chemotactic protein-1 (MCP-1)

 

This acts on chemokine receptors CCR2b on the monocytic stem cells.

 

 There is some similarity to granulomatous diseases like tuberculosis and the organ dysfunction occurs because there are enough inflammatory cells (T cells and mononuclear phagocytes with noncaseating epithelioid cells) to distort the architecture of the organs involved.

 

Macrophages produce the 1,25 dihydoxy cholecalciferol from precursor 25 hydoxy cholecalciferol, and also make platelet derived growth factor, fibronectin and insulin-like growth factor 1.

These macrophages possess the gene for production of 25-hydoxy D3 1-alpha hydroxylase.

 

The excessive 1,25 dihydroxy D3 enhances calcium absorption sometimes producing hypercalcaemia, hypercalcuria and suppressing parathyroid hormone (PTH), but this causes renal disease in only a few percent of sarcoid cases.

 

Interleukin 2 almost certainly aids the ongoing T helper cell accumulation but other T cells are not over-active.

 

IL2 is a T cell growth factor, and probably accounts for the accumulation of the T helper cells in all the involved organs. (CD+4/CD8+can be 10/1, when it is normally 2/1)

 

 If interferon gamma is also increased, it recruits the other mononuclear phagocytes into tissue sites and it could contribute to fatigue as a number of interferons have been found to cause a very exhausted feeling when they are infused.

 

As mentioned, some 80% of sarcoidosis patients are markedly fatigued.

 

It is noted that although sarcoidosis is characterized by hyperglobulinaemia, including IgM anti T cell antibodies, this is thought to be a non-specific polyclonal stimulation of B cells and it does not seem to take part in the pathology.

 

 

Investigations.

 

Raised angiotensin converting enzyme (70%), mild lymphopenia, raised ESR, eosinophilia, hilar nodes on CXR, reticulonodular opacities in lung fields (about 90% have some CXR abnormality)

ACE can be high in other granulomatous disease.

 

Aspects of management.

 

About 50% resolve with minimal treatment.

 

Glucocorticoids inhibit inflammation, suppress activated T helper cells, reduce granulomata and reduce macrophage production of 1,25 D3, thus reversing hypercalcaemia.

 

I recommend changing fatty acids so as to increase the omega 9 (olive) and omega 3 (linseed, canola and fish oils) and to decrease the poly unsaturates of the omega 6 kind. 

 

 I also recommend taking some vitamin E, about 500 IU/day (this should include mixed tocopherols), and probably some co enzyme Q10 which is protective and reparative to mitochondrial DNA.

 

 Also increase intake of vitamin C and flavonoids as this has the capability of improving normal immune responses. 

 

I would recommend 200-300 mgm of elemental magnesium a day because this contributes to relaxing smooth muscles in arteries and can improve sleep. 

 

A supplement of zinc of the order of 20 mgm a day is probably worthwhile as well and also I think it is worth getting gut flora into as optimal a state as possible by using supplementary lacto bacilli and fructooligosaccharide. 

 

Ginger has anti-inflammatory activity, as does ginkgo biloba, willow bark and feverfew and ginkgo and onion have some steroid-like effect in inhibiting phospholipase A2, and decreasing platelet activating factor.

 

Quercetin has promise by inhibition of PLA2, lipoxygenases, and matrix metalloproteinases (MMPases) (See notes on quercetin)

 

Trevor Marshall Ph d from California reports the following.

“Tiny 'pleomorphic' bacteria have been photographed living within the cells of the immune system of sarcoidosis patients. Emil and Barbara Wirostko produced stunning electron microscope photographs of immune phagocytes each containing hundreds of tiny bacterial forms, around 0.01 - 0.025 microns in diameter, living in colonies within the very cells (phagocytes), which are supposed to kill these bacterial parasites.

 

One of the Wirostko photographs can be found at URL http://www.autoimmunityresearch.org/wirostko-fig3.jpg

It is important to understand that these bacteria are 'coccoid' (round, and very, very, small), 10 to 100 times smaller than the shapes these same pleomorphic bacteria will take when they enter the bloodstream.

 

We found that you can measure a hormone (in the blood) resulting from the Th1 inflammation produced by these tiny bacteria, and that it is elevated in Sarcoidosis patients. It is also often elevated in CFS patients, indicating that the inflammation of CFS is often very similar to that of Sarcoidosis.

 

Angiotensin II (A-II) has profound actions in Th1 immune disease. Angiotensin II directly modulates the production of Nuclear Factor-kappaB (NF-kappaB) in the cytoplasm of mature phagocytes, causing nuclear release of messenger RNA (mRNA) to begin the transcription for many of the inflammatory chemokines and cytokines, including IL-1beta, IL-6, and IL-8, MCP-1, CAM-1, IFN-gamma and TNF-alpha. The blockade of the A-II modulation pathway with Angiotensin II Type 1 Receptor Blockers (ARBs) reduces the generation of these cytokines, including TNF-alpha, and inhibits the inflammatory process.

 

In the light of new knowledge that Th1 inflammatory disease can be caused by bacterial pathogens, we need to determine whether ARBs might also be exerting any direct antibacterial action upon the pathogenic bacteria.

 

The two hormones critical to this inflammatory process are Angiotensin II and the seco-steroid 1,25-dihydroxyvitamin-D.

Blockade of Angiotensin II weakens these bacteria to the point where they can be more easily killed, and reducing the 1,25-D makes it harder for the bacteria to slip in and out of the cells they have infected.”

 

More recently he has reviewed the molecular models of receptors and their ligands and writes that the evidence suggests that 25 D3 is a blocker on the 1,25 D3 receptor. Thus he now emphasizes that lowering the 25 D3 to 20ng/ml is important.

If we do this we need to be sure that we do not render the person D deficient, so monitoring PTH is important.

 

 Marshall is suggesting that angiotensin 2 receptor blockers (especially olmesartan, which also appears to block CCR2b receptors, and may be a 1,25 D3 agonist). His plan includes limiting dietary D3 and decreasing 1,25 dihydroxy D3 (sun avoidance), and adding antibiotics slowly, are the main requirements.

I do not let vitamin 25 D3 fall to low levels.

He is concerned that release of TH1 cytokines can be provoked by antibiotic induced bacterial destruction (Herxheimer like reactions)

This leads him to a slow introduction and gradual increase in the antibiotics that are effective against intracellular cell wall deficient bacteria.

This reaction may be a risk in Lyme disease and syphilis but is less likely in other intracellular bacterial infections.

 

For the technically minded doctor.

 

The bacterial ribosome is designated 70S

 

Tetracyclines interact reversibly with the bacterial 30S ribosomal subunit, blocking the binding of aminoacyl tRNA to the messenger RNA-ribosome complex. The specificity for bacterial and mycoplasmal ribosomes relates to their requirement for active, energy dependent transport into the bacterial cell by a system not found in mammalian cells.

 

A recent discovery that tetracyclines inhibit metalloproteinases such as collagenases may emerge as another therapeutic avenue in inflammatory states.

 

Macrolides and ketolides bind to the 23S location of the 50S ribosomal subunit, while lincosamides (e.g. Clindamycin also on the 50S site), aminoglycosides, and mupirocin also work in different ways to inhibit protein synthesis in bacterial cells.

 

The ketolide, telithromycin may be very useful with resistant organisms.

 

Rifampicin, metronidazole, and quinolones all inhibit DNA synthesis.

 

Rifampicin inhibits bacterial DNA polymerase. It is a potent inducer of CYP450 enzymes.

 

There is major and I would claim, excessive use of antibiotics in animal husbandry.

 

Because of the difficulty of clearing Rickettsiae, I note that Schlunzen and colleagues found that chloramphenicol, clindamycin and the macrolides erythromycin, clarithromycin and roxithromycin bind exclusively to the segments of the 23 S ribosomal RNA at the peptidyl transferase cavity and do not involve any interaction with ribosomal proteins.

 

Chloramphenicol does block the enzyme activity, but is almost never used in human diseases because of the rare bone marrow aplasia that can result.

 

Macrolides do not block the peptidyl transferase activity, even if they bind with the enzyme, but seem to block the tunnel that channels the nascent peptides away from the peptidyl transferase centre.

Research into the exact structure of macrolides reveals mechanisms by which ribosomal resistance develops in these organisms.

 

Macrolides tend to have three structural components: the lactone ring, the desosamine sugar, and the cladinose sugar.

The reactive groups of the desosamine sugar and the lactone ring mediate all the hydrogen bond interactions of erythromycin, clarithromycin and roxithromycin with the peptidyltransferase cavity.

 

It appears that Mg 2+ ions are important at these binding sites.

The major metabolite, 14 hydroxy clarithromycin is more active than clarithromycin against the spotted fever group of rickettsiae.

The ketolide, telithromycin may be very useful with resistant organisms, as it binds more tightly to ribosomes.

                                                                         

Another macrolide, tylosin, does inhibit peptidyl transferase.

Josamycin has also been used successfully for rickettsial disease.

                                                                       

Quinolones corrupt activity of two essential enzymes, DNA gyrase and topoisomerase IV in the organisms, inducing them to kill cells by generating high numbers of double strand DNA breaks. Ciprofloxacin is a type I quinolone which works in this way.

 

Warnings have emerged that fluoroquinolones increase the risk of tendon rupture.

 

I have highlighted these actions with particular reference to intracellular bacteria that have been implicated in sarcoidosis and CFS.                 

 

In regards to Rickettsiae, Cecile Jadine recommends one week on and three weeks off with these antibiotic courses. It seems to be important to alternate these agents.

The science of optimum use has yet to be adequately developed.

 

The same thing is true for mycoplasma infection.

 

It is very likely that chronic infection requires more courses because the organism can persist inside cells in a dormant state.

 

I would consider minocycline and azithromycin in chronic cases, because of the high intracellular penetration of these antibiotics, and these are the main ones used by the Marshall Protocol.

Thus if he turns out to be right, the Marshall Protocol <http://www.marshallprotocol.com/>may be crucial to better outcomes.

 

In fact I do not think Marshall has proven his regime, despite his brilliant computer generated images.

 

I am concerned to not let the vitamin D3 levels fall to subnormal levels!

 

Quercetin may improve sarcoidosis, and is probably steroid sparing.

 

Curcumin in turmeric inhibits NF kappa beta activation, thus decreasing TH1 cytokines

 

There is also the possibility of trying some Lyprinol which is a series of eicosatetraenoic acids from the New Zealand green lipped mussel capable of inhibiting 5 lipoxygenase and therefore reducing amounts of leucotrienes A4, B4, C4, D4 and E4.

 

 Leucotriene B4 is pro-oedematous and chemotactic for cells such as eosinophils and polymorphs under various circumstances and that leucotrienes C4, D4 and E4 are more bronchospastic than histamine.  A dose of about 3-7 capsules a day would be suggested from research so far. *

                                               

I turn to the optimization of immune responses.  In rheumatoid arthritis for example some circulating IgG antibodies bear malformed glycoproteins.   Terminal galactose molecules are missing from these structures and with more severe disease there is a greater abnormality in the glycoprotein.

 

Acetylated mannans seem to have some important signaling role at T cell and other receptor sites.  Mannose binding protein is an early form of defence against viral bacterial or fungal infections.

 

At this stage it is fairly conjectural but there is some evidence that pesticides interfere with some human enzymes and may make for abnormal immune responses.  Providing some of the rarer plant sugars namely mannose, fucose, N acetyl galactosamine, N acetyl glucosamine, xylose and acetyl neurominic acid has been shown to improve health in systemic lupus at the same time as natural killer cell function work better and viral loads were reduced and this has also been demonstrated in some chronic fatigue (Associate Professor Darryl See, University of California at Irvine).

 

Any hepatic steatosis means a need to reverse any hyperinsulinaemia and in particular to reduce fructose and sucrose intake.

 

I have no scientific data to support the use of glyconutrients,

 

 To summarize, I favour

(1)            Optimize nutrition, and reverse hyperinsulinaemia. Nutrition is a serious issue in persons with lap banding. It is crucial to have an adequate protein intake, and I would add acetyl-l-carnitine if there is any chance of this being low.

(2)            I am aiming to protect the Krebs cycle and mitochondrial function.

(3)            Minimizing sucrose and fructose is important.

(4)            Optimize vitamin D3 and 1,25 D3 levels

(5)            Add olmesartan, increasing slowly from 20mg bd up to 20mg 3-4 times per day and even higher if tolerated.

This is to block the CCR2b receptor, since the Ki value for olmesartan for the CCR2b receptor is 9 (for the A2R receptor the Ki value is 0.9.)

Any number under 10 means significant affinity for the receptor.

(6)            Increase fish oil, co-enzyme Q10, turmeric (and black pepper which enhances the absorption of the Q10 and the curcumin)

(7)            Consider appropriate trials of above antibiotics.

(8)            Maintain normal gut flora.

 

 

 

* Dr Henry Betts T QEH

 

        Related Articles, Links

 

References.

 

Harrison’s Principles of Internal Medicine (16^th edition) P2017-2023

 

Monkawa T, Yoshida T, Hayashi M, Saruta T.

Identification of 25-hydroxyvitamin D3 1alpha-hydroxylase gene expression in macrophages.

 

Kidney Int. 2000 Aug;58(2):559-68.

 

Marshall TG, Fenter B, Marshall FE: Putative Antibacterial Mechanisms for Angiotensin II Receptor Blockers. JOIMR 2004;2(2):1

 

 

 Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J: Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells - molecular mechanisms. Circ Res. 2000, 86(12):1266-72. PMID: 10864918

Available from URL http://circres.ahajournals.org/cgi/content/full/86/12/1266 Accessed 7 May 2004.

 Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3):2

Available from URL http://www.joimr.org/phorum/read.php?f=2&i=38&t=38 Accessed 7 May 2004

 

 Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics - implications for autoimmune disease. Autoimmun Rev. 2004 Jun;3(4):295-300 PMID: 15246025 [Pubmed Abstract],[Full Text Preprint]

 

 De Bosscher K, Vanden Berghe W, Vermeulen L, Plaisance S, Boone E, Haegeman G: Glucocorticoids repress NF-kB -driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell. Proc Natl Acad Sci U S A 2000, 97(8): 3919-2 PMID: 10760263

Shi GX, Harrison K, Han SB, Moratz C, Kehrl JH: Toll-like receptor signaling alters the expression of regulator of g protein signaling proteins in dendritic cells: implications for G protein-coupled receptor signaling. J Immunol. 2004 May 1;172(9):5175-84. PMID: 15100254

 

 Miyake K: Innate recognition of lipopolysaccharide by Toll-like receptor 4-MD-2. Trends Microbiol. 2004 Apr;12(4):186-92. PMID: 15051069

 

 Nagai S, Takeuchi M, MorEur Respir J. 2002 Nov;20(5):1206-12.

  Links

CC and C chemokine expression in pulmonary sarcoidosis.

        Petrek M, Kolek V, Szotkowska J, du Bois RM.

Dept of Immunology, Palacky University and University Hospital, Olomouc, Czech Republic. petrekm@fnol.cz

ita K, Mikuniya T, Satake N, Mio T, Izumi T: Angiotensin II receptor on BALF macrophages from Japanese patients with active sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 1999 Mar;16(1):67-74. PMID: 10207944 Nippon Rinsho. 2002 Sep;60(9):1728-33.

Links

[Mechanism of sarcoid granuloma formation--participation of cytokines and chemokines]

[Article in Japanese]

        Sugiyama Y, Oshikawa K.

Division of Pulmonary Medicine, Department of Medicine, Jichi Medical School.

In sarcoidosis, unknown antigen(s) causes Th1-mediated granulomatous inflammation with cytokines such as IFN gamma and IL-12, initially. IL-16, IL-8, IP-10 and RANTES are participated in the accumulation of CD4+ T cell. For the chemotaxis of macrophages and monocytes, MCP-1, MIP1-alpha and RANTES are participated. Local proliferation of T cell is induced by IL-2 and IL-15 and that of macrophage/monocyte lineage is done by M-CSF, GM-CSF and G-CSF. Removal of the causative antigen(s) allows immune-suppressive cytokines such as TGF beta to downregulate the immune response and granuloma formation. Failure of removal of causative antigen(s) can induce prolonged existence of granuloma and irreversible fibrosis.

 

Role of monocyte chemoattractant protein-1 in Propionibacterium acnes-induced pulmonary granulomatosis.

        Ichiyasu H, Suga M, Iyonaga K, Ando M.

First Department of Internal Medicine, Kumamoto University School of Medicine, Kumamoto, Japan.