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editorials: Marc A. Judson The Etiologic Agent of Sarcoidosis: What If There Isn’t One? Chest 2003; 124: 6-8 [Full text] [PDF]

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Sarcoid Inflammation has a Primary, Homogeneous, Bacterial Pathogenesis

Trevor G Marshall   (4 August 2003)

Sarcoid Inflammation has a Primary, Homogeneous, Bacterial Pathogenesis 4 August 2003
Trevor G Marshall, Managing Editor JOIMR.org Send letter to journal: Re: Sarcoid Inflammation has a Primary, Homogeneous, Bacterial Pathogenesis Trevor.M{at}JOIMR.org Trevor G Marshall	In his July 2003 Editorial, Dr. Judson writes: "the evidence suggests the immunologic process that leads to sarcoidosis begins when an antigen is presented to a macrophage via HLA class II molecules to a T Lymphocyte. This induces a Th1 T-lymphocyte response whereby cytokines are released that result in granuloma formation"[1]. However, if the evidence really suggested this antigenic etiology then why has a century of research failed to definitively identify how these processes could ever result in the characteristic pathology of the sarcoid granuloma? Further, while this description implies that the Th1 cytokine cascade should be associated with high levels of T-lymphocytes, the opposite is true:- advanced cases of sarcoid inflammation present with T-lymphopenia [2]. I have just published a review paper [3] which is an overview of our first year's experience successfully using antibiotic therapy to induce remission in sarcoidosis. The review's full text deals with many of the issues raised by Dr Judson. Firstly, the conventional description (above) is based on an understanding of the immune system of healthy individuals, and it fails to describe the immune system of patients with sarcoidosis because the factors at work in immune disease are different from those at work in a healthy individual. The presence of cell-dwelling pathogens creates an entirely different immune environment, one where it is the pathogens 'calling the tune', and where the conventional sequence of T-lymphocyte-to-antigen challenge is no longer the driving force. Cell-dwelling pathogens cause Th1 immune disease by utilizing an ability to mimic the T-cell Receptor alpha-beta V protein [4]. They are thus capable of directly activating the 'host' monocytes, macrophages and giant-cells which they have parasitized. A cascade of cytokines and chemokines is then continuously released, directly by the parasitized 'host' cells, without the need for any activated T-lymphocytes to be present. The SARS Coronavirus is a pathogen with the apparent ability to virulently hyper-activate the immune system in this manner [4,5,6]. While the granuloma of sarcoidosis are formed by an accumulation of considerably less virulent pathogens than SARS, the anomalous T-cell Receptor alpha-beta V protein is similarly present [7]. The granuloma of sarcoidosis are formed within inflamed tissue when sufficient lymphopenia-inducing parasites have colonized the monocytes, macrophages and giant-cells in order to sustain a self-activated and non-necrotic inflammatory core [8]. The un-needed T-lymphocytes are down-regulated and expelled to the granuloma's periphery, forming the characteristic non-caseating granulomatous pathology of Sarcoidosis. Secondly, I would point out that Drake, et al., recently explained in their CDC "Emerging Infectious Diseases" paper [9] exactly why so many studies have failed to find mycobacteria in sarcoidosis tissues. The IS6110 sequences, which are a characteristic of the active mycobacterium spirochete, are just not found in the cell-wall-deficient, tissue dwelling, variant(s) of this species which are active in sarcoidosis. Additionally I am surprised by the presentation of Prof. Cadranel's research [10] in support of a lack of bacterial etiology. The HAART-induced transition of a patient's disease state from a viral HIV infection to one of sarcoidosis is, in fact, an extremely persuasive demonstration that sarcoidosis has a bacterial pathogenesis... Immune disease is not a sudden switch from one disease state to another, it is characterized by an orderly and gradual transition. Mawer, et al., observed that serum 1,25-dihydroxyvitamin-D (1,25-D) gradually dropped in Breast Cancer patients with a poor prognosis [11]. This secosteroid hormone is an excellent marker for Th1 immune activity, and as the immune system's Th1 activity becomes overwhelmed by the Th2 of the cancerous cells, the level of 1,25-D drops. Lauerova, et al., confirmed that the same gradual transition between Th1 and Th2 can be observed in Malignant Melanoma [12], and the prognosis is again related to the degree of Th1 reaction which the body can mount. As the HIV virus overwhelms the body's Th1 immune defenses then the level of 1,25-D falls to very low values. In many cases it becomes unmeasurable. 1,25-D is the key hormone responsible for differentiation of hematopoetic cells into monocytes, and then also for monocyte differentiation into macrophages and giant-cells. In its absence,the granulomas of sarcoidosis cannot form. Although the cell-dwelling parasites (which would normally cause sarcoidosis) are still present, the disease is unable to manifest itself because the body has no remaining 1,25-D to differentiate hematopoetic cells into the monocytes it needs to fight those parasites. As the HIV virus causing the Th2 response is killed off by HAART then the body is able to again mount its Th1 response, and the Th1 monocytes (which will eventually be parasitized by the CWD bacteria into the granuloma of Sarcoidosis) can again be formed. The patient's body is facing a continuum of immune challenges, and not just facing a series of disconnected disease states. My mind no longer harbors any doubt that sarcoid inflammation has a primary, homogeneous, bacterial pathogenesis. I have been following the progress of a heterogeneous mix of over 50 neurosarcoidosis, cutaneous sarcoidosis, and pulmonary sarcoidosis patients, some chronic (wheelchair-bound), and some newly diagnosed. With few exceptions, all report Herxheimer (and improvement) primarily induced by minocycline/doxycycline antibiotic therapy [3]. Trevor G Marshall, PhD 3 August 2003 1. Judson MA: The etiologic agent of sarcoidosis: what if there isn't one? Chest. 2003 Jul;124(1):6-8[PubMed Abstract] 2. Bergoin C, Lamblin C, Wallaert B: Biological manifestations of sarcoidosis. Ann Med Interne (Paris). 2001 Feb;152(1):34-8[PubMed Abstract] 3. Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3):2[Full Text] 4. Lee RE: SARS E2-spike Protein Contains a Superantigen Between Residues 690 through 1050. JOIMR 2003;1(1):3[Full Text] 5. Yu XJ, Luo C, Lin JC, Hao P, He YY, Guo ZM, Qin L, Su J, Liu BS, Huang Y, Nan P, Li CS, Xiong B, Luo XM, Zhao GP, Pei G, Chen KX, Shen X, Shen JH, Zou JP, He WZ, Shi TL, Zhong Y, Jiang HL, Li YX: Putative hAPN receptor binding sites in SARS-CoV spike protein. Acta Pharmacol Sin. 2003 Jun;24(6):481-8[PubMed Abstract] 6. Lee RE: SARS Coronavirus Appears to be an FcgammaR Agent, Causing an Hyperimmune Response via a CD13 pathway - Implication for Therapeutic Interventions. JOIMR 2003;1(1):2[Full Text] 7. Silver RF, Crystal RG, Moller DR: Limited heterogeneity of biased T-cell receptor V beta gene usage in lung but not blood T cells in active pulmonary sarcoidosis. Immunology. 1996 Aug;88(4):516-23[PubMed Abstract] 8. Marshall TG, Marshall FE: A Mechanism to Explain the T lymphopenia. BMJ Rapid Response 20 June 2003; #33479[Full Text] 9. Drake WP, Pei Z, Pride DT, Collins RD, Cover TL, Blaser MJ: Molecular analysis of sarcoidosis tissues for mycobacterium species DNA. Emerg Infect Dis. 2002 Nov;8(11):1334-41[Pubmed Abstract] 10. Naccache JM, Antoine M, Wislez M, Fleury-Feith J, Oksenhendler E, Mayaud C, Cadranel J: Sarcoid-like pulmonary disorder in human immunodeficiency virus-infected patients receiving antiretroviral therapy. Am J Respir Crit Care Med. 1999 Jun;159(6):2009-13[PubMed Abstract] 11. Mawer EB, Walls J, Howell A, Davies M, Ratcliffe WA, Bundred NJ: Serum 1,25-dihydroxyvitamin D may be related inversely to disease activity in breast cancer patients with bone metastases. J Clin Endocrinol Metab. 1997 Jan;82(1):118-22[PubMed Abstract] 12. Lauerova L, Dusek L, Simickova M, Kocak I, Vagundova M, Zaloudik J, Kovarik J: Malignant melanoma associates with Th1/Th2 imbalance that coincides with disease progression and immunotherapy response. Neoplasma. 2002;49(3):159-66[PubMed Abstract]