CAP for MS: Q&A and Peer Reviewed Support

A Beginners Guide to Combined Antibiotic Protocol for Multiple Sclerosis: Questions, Answers and Peer Reviewed Support

One of the problems with learning about various Multiple Sclerosis theories is the perception that they are in conflict with what we already know about MS. Another problem is that we often get non-authoritative or somewhat questionable support for explanations we are offered. I have assembled the following questions and answers in an effort to help others who are interested in Multiple Sclerosis to understand the reasoning behind the Combined Antibiotic Protocol and how bacterial theory can be compatible with autoimmune theory. Each link (with few exceptions) should take you to a COMPLETE peer reviewed article from a medical journal that supports the answers provided. Please let me know about any new questions you think should be included, bad links or ideas to improve the post. It is notable that there are a LOT more articles that might even be better than those I have referenced, however, I have tried to only use resources that are free, complete and authoritative.


Q: Isn’t apoptosisi supposed to protect my body from bacterial infection?
A: Yes, but it doesn’t always work. Your cells are pre-programmed to self-destruct when they become infected through a process called apoptosis. When infected by Chlamydia Pneumoniae, many human cells, including immune system cells, become hosts for the bacteria instead of working to destroy the bacteria. To be absolutely clear, CPni bacteria cell - living within your body's cell. It has even been shown that CPn infected host cells can proliferate via mitosis, creating more infected host cells.

Lancellotti, Marcelo et al. 2006 Bacteria-induced apoptosis: an approach to bacterial pathogenesis<
Geng, Yuemei et al. 2000 Chlamydia pneumoniae Inhibits Apoptosis in Human Peripheral Blood Mononuclear Cells Through Induction of IL-10<
Rajalingam, Krishnaraj et al. 2001 Epithelial Cells Infected with Chlamydophila pneumoniae (Chlamydia pneumoniae) Are Resistant to Apoptosis<
Fischer, Silke et al. 2004 Protection against CD95-Induced Apoptosis by Chlamydial Infection at a Mitochondrial Step<
Fischer, Silke et al. 2004 Chlamydia Inhibit Host Cell Apoptosis by Degradation of Proapoptotic BH3-only Proteins<
Green, Whitney et al. 2004 Chlamydia-Infected Cells Continue To Undergo Mitosis and Resist Induction of Apoptosis<
Sasu, Sebastian et al. 2001 Chlamydia pneumoniae and Chlamydial Heat Shock Protein 60 Stimulate Proliferation of Human Vascular Smooth Muscle Cells via Toll-Like Receptor 4 and p44/p42 Mitogen-Activated Protein Kinase Activation<

Q: Do my cells function differently after they become hosts for Chlamydia Pneumoniae?
A: Yes. Cellular expression can be dramatically altered. Genes related to apoptosis, the cell cycle and host metabolism are permanently differentially regulated by Chlamydia Pneumoniae. Chlamydia Pneumoniae has been shown to remain transcriptionally active while hosted by immune system cells. Infected human host cells have been found to significantly increase the release of interleukin (IL) 1b, IL-6, IL-8, IL-12, tumor necrosis factor alphai (TNF-a), intercellulari cell adhesion molecule 1(ICAM-1/CD54) and gamma interferon (IFN-y). These cytokinesi stimulate the immune system. In addition CPn activates nuclear factor kappa B (NF-kB) and down regulates major histocompatibility complex class I molecules (MHC-1).

Eickhoff, Meike et al. 2007 Host Cell Responses to Chlamydia pneumoniae in Gamma Interferon-Induced Persistence Overlap Those of Productive Infection and Are Linked to Genes Involved in Apoptosis, Cell Cycle, and Metabolism<
Krull, Matthias et al. 2004 Differences in Cell Activation by Chlamydophila pneumoniae and Chlamydia trachomatis Infection in Human Endothelial Cells<
Rupp, Jan et al. 2009 Chlamydia pneumoniae Hides inside Apoptotic Neutrophils to Silently Infect and Propagate in Macrophages<
Gencay, Mikael et al. 2003 Chlamydia pneumoniae Activates Epithelial Cell Proliferation via NF-κB and the Glucocorticoid Receptor<
Yang, Jun et al. 2003 Induction of Proinflammatory Cytokines in Human Lung Epithelial Cells during Chlamydia pneumoniae Infection<
Yamaguchi, Hiroyuki et al. 2002 Chlamydia pneumoniae Infection Induces Differentiation of Monocytes into Macrophages<
Rodel, Jurgen et al. 2000 Production of Basic Fibroblast Growth Factor and Interleukin 6 by Human Smooth Muscle Cells following Infection with Chlamydia pneumoniae<
Gaydos, Charlotte 2000 Growth in Vascular Cells and Cytokine Production by Chlamydia pneumoniae<


Q: Has anyone actually demonstrated a relationship between CPn bacteria and MS?
A: Yes, an excellent article was published in 1999 that effectively says that lots of folks with MS also have the CPn bacteria and the prevalence of the bacteria in folks with MS is significantly greater than average.

Sriram, Subramaniam et al. 1999 Chlamydia pneumoniae Infection of the Central Nervous System in Multiple Sclerosis<.

Q: Has CPn bacteria been identified in the central nervous system?
A: Yes, in fact CPn DNA has been identified in the brain and cerebrospinal fluid.

Sriram, Subramaniam et al. 2005 Detection of chlamydial bodies and antigens in the central nervous system of patients with multiple sclerosis<
Contini, Carlo et al. 2008 Chlamydophila pneumoniae DNA and mRNA transcript levels in peripheral blood mononuclear cells and cerebrospinal fluid of patients with multiple sclerosis<
Itzhaki, Ruth et al. 2004 Infiltration of the brain by pathogens causes Alzheimer’s disease<
Tang, Yi-Wei et al. 2009 Qualitative and Quantitative Detection of Chlamydophila pneumoniae DNA in Cerebrospinal Fluid from Multiple Sclerosis Patients and Controls<

Q: Can Chlamydia pneumoniae infect cellular hosts within the CNSi?
A: Yes, it has been demonstrated that CPn can infect and reproduce in microglial cells. Furthermore, CPn can sustain a chronic infection in neuronal cells by interfering with apoptosis.

Ikejima, Hideaki et al. 2006 Chlamydia pneumoniae infection of microglial cells in vitro: a model of microbial infection for neurological disease<
Appelt, Denah et al. 2008 Inhibition of apoptosis in neuronal cells infected with Chlamydophila (Chlamydia) pneumoniae<

Q: Have there been any studies that show how CPn infection can get out of the lungs?
A: Yes. It has been shown that infected Alveolar Macrophages can transmigrate through the mucosal barrier, thus giving Chlamydia Pneumoniae access to the lymphatic and systemic circulatory systems. It is also notable that Neutrophil Granulocytes (one of the first immune system cells to encounter CPn in the lungs) can host and incubate Chlamydia Pneumoniae.

Gieffers, Jens et al. 2004 Phagocytes transmit Chlamydia pneumoniae from the lungs to the vasculature<
Blasi, Francesco et al. 2004 Chlamydia pneumoniae: crossing the barriers?<
Van Zandbergen, Ger et al. 2004 Chlamydia pneumoniae Multiply in Neutrophil Granulocytes and Delay Their Spontaneous Apoptosis<
Rodriguez, Nuria et al. 2005 Polymorphonuclear Neutrophils Improve Replication of Chlamydia pneumoniae In Vivo upon MyD88-Dependent Attraction<

Q: Are there any studies that show the beneficial effect of antibiotics on MS?
A: Yes, there have been several studies that link antibiotics to improvement in patients with MS.

Brundula, Veronika et al. 2002 Targeting leukocyte MMPs and transmigration: Minocycline as a potential therapy for multiple sclerosis<
Minagar, Alireza et al. 2007 Combination Therapy With Interferon Beta-1a and Doxycycline in Multiple Sclerosis<

Q: A lot of folks are just taking Minocycline, why are multiple antibiotics required in the protocol?
A: While Minocycline is a tetracycline that can work against CPn, it cannot kill CPn in all three phases of its life cycle: elementary body, reticulate body and cryptic formi. Rifampin in combination with Azithromycin has been found to be more effective than single antibiotic therapy.

Wolf, Katerina et al. 1999 Effect of Azithromycin plus Rifampin versus That of Azithromycin Alone on the Eradication of Chlamydia pneumoniae from Lung Tissue in Experimental Pneumonitis<.

However duel therapy does not eliminate CPn in its cryptic form, which is also referred to as persistent, nonreplicating, aberrant and refractory. The addition of a third antibiotic is needed to completely eliminate CPn bacteria from the body.

Gieffers, Jens et al. 2001 Chlamydia pneumoniae Infection in Circulating Human Monocytes Is Refractory to Antibiotic Treatment<
Hogan, Richard et al. 2004 Chlamydial Persistence: beyond the Biphasic Paradigm<
Mukhopadhyay, Sanghamitra et al. 2006 Protein Expression Profiles of Chlamydia pneumoniae in Models of Persistence versus Those of Heat Shock Stress Response<

Q: When taking antibiotics, does dosage really matter?
A: Yes, not following dosage frequency and amounts can induce persistence.
Gieffers, Jens et al. 2004 First-Choice Antibiotics at Subinhibitory Concentrations Induce Persistence of Chlamydia pneumoniae<.


Q: Does the way MMP-9 has been implicated in MS correlate with CPn infection?
A: Yes it does. Increased MMP-9 expression has been demonstrated in MS and MMP-9 has been shown to disrupt myelini and cause demyelinationi. Chlamydia Pneumoniae has been found to stimulate the production of MMP-9 in macrophages.

Leppert, David et al. 1998 Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis<
Yong, V. Wee et al. 2001 Metalloproteinases in Biology and Pathology of the Nervous System<
Vehmaan-Kreula, Pirjo et al. 2001 Chlamydia pneumoniae Proteins Induce Secretion of the 92-kDa Gelatinase by Human Monocyte–Derived Macrophages<

Q: Does the way IL-6 has been implicated in MS correlate with CPn infection?
A: Yes it does. CPn infection is known to upregulate IL-6 and IL-6 is known to be proinflammatory in MS. In an MS related illness, Transverse Myelitis, there is evidence that IL-6 causes demyelination and axonal injury.

Dasgupta, Subhajit et al. 2003 Role of Very-late Antigen-4 (VLA-4) in Myelin Basic Protein-primed T Cell Contact-induced Expression of Proinflammatory Cytokines in Microglial Cells<
Kaplin, Adam et al. 2005 IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis<
Johnston, S. Claiborne et al. 2005 Chlamydia pneumoniae Burden in Carotid Arteries Is Associated With Upregulation of Plaque Interleukin-6 and Elevated C-Reactive Protein in Serum<

Q: Does the way ICAM-1 has been implicated in MS correlate with CPn infection?
A: Yes. ICAM-1 is barely detectable in the normal brain. However, increased expression of ICAM-1 has been shown on endothelial cells, microglia and astrocytes in active MS. More specifically, ICAM-1 has been shown to be crucial for leukocyte infiltration into the brain, and the process of migration across the brain endothelial layer can accelerate the breakdown of the blood brain barrier. Several lines of evidence indicate that ICAM-1 acts as a docking molecule for lymphocytes before migration. ICAM-1 further facilitates transmigration through the CNS endothelium by rearrangement of the endothelial actin cytoskeleton, meaning ICAM-1 stimulates the altering of the impermeable tight junctions of the blood brain barrier. Chlamydia Pneumoniae can infect human endothelial cells where it induces the expression of ICAM-1, which has also been linked to monocyte migration.

Etienne-Manneville, Sandrine et al. 2000 ICAM-1-Coupled Cytoskeletal Rearrangements and Transendothelial Lymphocyte Migration Involve Intracellular Calcium Signaling in Brain Endothelial Cell Lines<
Bullard, Daniel et al. 2007 Intercellular Adhesion Molecule-1 Expression Is Required on Multiple Cell Types for the Development of Experimental Autoimmune Encephalomyelitis<
Dai, Jianfeng et al. 2008 ICAM-1 Participates in the Entry of West Nile Virus into the Central Nervous System<
Adamson, Peter et al. 1999 Lymphocyte Migration Through Brain Endothelial Cell Monolayers Involves Signaling Through Endothelial ICAM-1 Via a Rho-Dependent Pathway<
Buul, Jaap et al. 2004 Signaling in Leukocyte Transendothelial Migration<
Lawson, Charlotte et al. 2009 ICAM-1 signaling in endothelial cells<
Kol, Amir et al. 1999 Chlamydial and human heat shock protein 60s activate human vascular endothelium, smooth muscle cells, and macrophages<
Vielma, Silvana et al. 2003 Chlamydophila pneumoniae Induces ICAM-1 Expression in Human Aortic Endothelial Cells via Protein Kinase C–Dependent Activation of Nuclear Factor- B< 

Q: Does the way Immunoglobulin G antibodies (IgGi) have been implicated in MS correlate with CPn infection?
A: Yes. The detection of elevated IgG in Cerebral Spinal Fluid (CSF) via oligoclonal bands has an extensive association with the diagnosis of MS by lumbar puncture. In fact, unique antibody patterns have been associated with the different types of MS and IgG from MS patients may provoke T-cell response. Likewise, anti-Chlamydia Pneumoniae antibodies (IgG) have been associated with MS. These have been identified in the CSF of MS patients and been shown to have greater gene transcription. Interestingly, it has also been shown that CPn infection can lead to an accumulation of IgG within an infected cell, which potentially correlates with increased IgG populations in patients with a longer history of MS.

Ezio Paolino et al. 1996 A prospective study on the predictive value of CSF oligoclonal bands and MRI in acute isolated neurological syndromes for subsequent progression to multiple sclerosis<
Francisco Quintana et al. 2008 Antigen microarrays identify unique serum autoantibody signatures in clinical and pathologic subtypes of multiple sclerosis<
Holmoy, Trygve et al. 2003 T cells from multiple sclerosis patients recognize immunoglobulin G from cerebrospinal fluid< (abstract only)
Enrico, Fainardi et al. 2008 Under the microscope: focus on Chlamydia pneumoniae infection and multiple sclerosis< (abstract only)
Dong-Si, Tuan et al. 2004 Increased prevalence of and gene transcription by Chlamydia pneumoniae in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis<
Yao, Song-Yi et al. 2001 CSF oligoclonal bands in MS include antibodies against Chlamydophila antigens<
Pollack, David et al. 2008 Uptake and intra-inclusion accumulation of exogenous immunoglobulin by Chlamydia-infected cells<
Owens, Gregory et al. 2003 Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid<

Q: Does the way IFN-y {gamma} has been implicated in MS correlate with CPn infection?
A: Yes it does. IFN-y has been associated with exacerbations and oligodenrocyte death. It has been shown that IFN-y expression plays a central role in the bodys effort to control Chlamydia Pneumoniae infection.

Panitch, Hillel et al. 1987 Treatment of multiple sclerosis with gamma interferon<
Mana, Paula et al. 2006 Deleterious Role of IFN in a Toxic Model of Central Nervous System Demyelination<
Rottenberg, Martin et al. 2000 Regulation and Role of IFN-y in the Innate Resistance to Infection with Chlamydia pneumoniae<

Q: Monocytes have been implicated in MS. How does this relate to CPn infection?
A: Monocytes have been found to migrate across the blood brain barrier and contribute to inflammationi. Some benefits associated with MS therapies have been linked to their targeting monocytes. Monocytes are easily infected with CPn and can disseminate CPn within systemic circulation.

Bar-Or, Amit et al. 2003 Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis<
Kopadze, Ted et al. 2006 Inhibition by Mitoxantrone of In Vitro Migration of Immunocompetent Cells: A Possible Mechanism for Therapeutic Efficacy in the Treatment of Multiple Sclerosis<
Minagar, Alireza et al. 2008 Combination Therapy With Interferon Beta-1a and Doxycycline in Multiple Sclerosis: An Open-Label Trial<
Burger, Danielle et al. 2009 Glatiramer acetate increases IL-1 receptor antagonist but decreases T cell-induced IL-1β in human monocytes and multiple sclerosis<
Hakki, Amal et al. 2007 Chlamydia pneumoniae infection modulates cytokine production by human T lymphocytes and monocytes<
Gieffers, Jens et al. 2001 Chlamydia pneumoniae Infection in Circulating Human Monocytes Is Refractory to Antibiotic Treatment<

Q: Besides monocytes, do other immune system cells have behavior that correlates between MS and CPn infection?
A: Lymphocytes are also a major group of immune system cells that exhibit potentially corroborating behavior in MS and CPn infection. T-Lymphocyte and B-Lymphocyte migration through the brain endothelium/blood brain barrier has been associated with Multiple Sclerosis. Chlamydia Pneumoniae has been shown to infect and multiply in Lymphocytes. CPn infected Lymphocytes have been shown to be resistant to some antibiotic therapies.

Alter, Andrea et al. 2003 Determinants of Human B Cell Migration Across Brain Endothelial Cells<
Prat, Alexandre et al. 2002 Migration of Multiple Sclerosis Lymphocytes Through Brain Endothelium<
Haranaga, Shusaku et al. 2001 Chlamydia pneumoniae Infects and Multiplies in Lymphocytes In Vitro<
Yamaguchi, Hiroyuki et al. 2003 Chlamydia pneumoniae Resists Antibiotics in Lymphocytes<


Q: Has it been proven that MS is an autoimmune illness?
A: No. While science has pursued autoimmune theory for decades, it has yet to be proven that the underlying cause of MS is initiated or perpetuated through autoimmunityi.
Chaudhuri, Abhijit et al. 2005 Multiple sclerosis: looking beyond autoimmunity<