The human immune system is composed of two types of immune response systems that work together to protect the body against bacteria, viruses and other disease-causing agents, and to detect, control and fight abnormal cells, such as cancer cells.
is a link to a fascinating diagram comparing the sizes of cells and molecules – use the slider underneath.
The innate immune system recognizes molecules produced by foreign invaders, or pathogens. When it detects one of these foreign molecules, it produces an innate immune response to rapidly contain an infection and to limit its spread, until a more specific adaptive immune response can be made to eliminate the pathogen.
Innate immunity is nonspecific and does not change with repeated exposures to a substance. In a normally functioning immune system, the innate immune system can very rapidly respond to injury through producing an inflammatory response.
The innate immune system includes physical and chemical barriers, like the skin and low pH, and also interferons and complement. It includes particular cell types, such as phagocytic cells - neutrophils, dendritic cells and macrophages, as well as natural killer (NK) cells. Rather than recognizing specific antigens, these cells recognize broad categories of organisms/antigens through other means, such as complement binding or toll-like receptors. For instance, toll-like receptor 2 (TLR-2) and TLR4 allow phagocytic cells to recognize bacteria. Cathelicidin Anti Microbial Peptide (CAMP) is just one of several natural antibiotics produced by the Vitamin D receptor (VDR) when innate immunity is activated.
The adaptive immune system is activated by the innate immune response, recognizes antigens unique to particular pathogens, and produces a long-lasting adaptive immune response specific to that pathogen (or antigen associated with the pathogen).
Adaptive immunity is very specific and does lead to an increase in response with repeated exposures. Exposure to a particular substance, an antigen from a bacterium, for example, will lead to a faster, more effective response to that particular antigen in the future, but not to any other antigens. It will lead to the creation of memory T lymphocytes and memory B cells that will then be available to "remember" a particular species of pathogen or other antigenic substance, so that the response will be more effective and rapid on subsequent exposure.
Depending on the nature of the innate immune response, either or both antibodies and specific killer T cells can be included within the adaptive immune response. The response includes both fighting the existing pathogen and generating the ability to recognize and respond more rapidly to a subsequent encounter with the same pathogen. Once initiated, adaptive immunity is boosted or re-triggered simply by exposure to the antigen again.
Despite the division into two categories, it is important to remember that the innate and adaptive immune systems are not really separate, but interact in many ways. For instance, the adaptive immune response makes the innate immune responses, such as macrophage function, much more efficient. An example of this interaction is cell mediated immunity. This occurs when Th1 lymphocytes of the adaptive immune system are stimulated by specific antigens and other substances to produce interferon gamma. The interferon gamma causes macrophages to become activated and produce more TNF alpha. More macrophages are attracted to the area and a very strong immune reaction may occur that may even damage surrounding tissue. In fact, this is the type of reaction that is known to occur in tuberculosis, leading to granuloma formation. In the later stages of some Th1 diseases, like sarcoidosis, after a while, the macrophages become very abundant and the adaptive immunity becomes weak, leaving the innate immune response as the primary relevant factor in granuloma formation and perpetuation.
T helper cells
Th1 is short for T helper cell type 1 (a type of lymphocyte or white cell). Th1 responses generate killer T cells and certain antibodies, important in fighting intracellular pathogens and intracellular defects, such as cancers.
Th17 is short for Interleukin (IL)-17-producing T helper cells. Th17 cells are a recently identified subset, separate from the T helper type 1 (Th1) and T helper type 2 (Th2) subsets (see below). They arise in the presence of infection, and are also associated with what are viewed as autoimmune conditions.
For more information about Th17 helper cells, see:
Innate immune recognition of infected apoptotic cells directs Th17 cell differentiation
"Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defence against the invading pathogen."
Responding to infection and apoptosis--a task for Th17 cells.
Th17 cells in the setting of Aspergillus infection and pathology
"Several experimental studies and clinical investigations confirmed that IL-23-driven Th17 cells, rather than the Th1-cell subset, mediate the inflammatory responses of autoimmune or infectious origin."
Both a Th1 and a Th17 response is mounted by the immune system to eliminate intracellular pathogens.
Th2 is short for T helper cell type 2. A Th2 response is used to fight off extracellular pathogens. Th2 responses generate specific types of antibodies, and are typical of allergic reactions, in which an allergen is mistaken for a pathogen, triggering an immune system response resulting in allergy symptoms. Although Th2 responses are important for defense against extracellular pathogens, they are not particularly helpful for fighting intracellular pathogens.
This tutorial contains basic information on T-Helper cells.
Th1 vs. Th2 response
Th1 inflammatory diseases are defined as characterized by high levels of Interferon-gamma in the inflamed tissue which catalyzes production of 1,25-D by the mitochondria of the activated macrophages. Determining Th1 disease versus Th2 must include measuring cytokines in paracrine tissue (not in venous blood), measuring Interferon-gamma and understanding the underlying molecular biology. A good proxy indicator for activation of the innate immune system, which is also available in a clinical setting, is 1,25-dihydroxyvitamin-D.
Th1 and Th2 immune responses are highly interdependent. A Th2 response may be activated by the cytokine storm from Th1 pathogens. The resulting antibodies have been mistakenly labeled 'autoimmune'. Any activity of the Th2 cytokines in chronic disease is a result of the primary Th1-inducing pathogens.
The use of TH1 and TH2 can be confusing and it now appears that the response we see is more accurately termed a TH17 response with chronic infection. Generally TH2 is thought of a an allergic presentation, but given the complexity of our immune systems lots of things can be going on at the same time.
The Th2 immune reaction of a healthy body does not generate much Interferon-gamma. This is important because Th1 immune reactions are often thought of as an 'over-active' immune system, because the Interferon-gamma, and the 1,25-dihydroxyvitamin-D it generates, cause extra mast cells to differentiate to monocytes (primitive white cells) and then to further differentiate (grow) into macrophages and dendritic cells, the most active phagocytes of the immune system (those cells which are charged with the job of digesting bacterial pathogens).
When the phagocytes become parasitized by Cell Wall Deficient variants of certain bacterial pathogens, it’s these pathogens which determine the body's immune response, not the T lymphocytes. The Th1 lymphocyte excitation is a result of the intracellular infection, and not a response to extracellular bacteria. This is because the bacteria within the cytoplasm of the phagocyte can directly force the nucleus of that cell to produce the Th1 cytokines, presumably as an advanced defense against the host (human).
In Th1 diseases, the transcription of antimicrobial peptides by the VDR Nuclear Receptor is inhibited by the pathogens. This lack of transcription is associated with an excess of Interferon-gamma (the Th1 marker) in the inflamed tissues. Generation of Interferon-gamma in a Th1 activated macrophage catalyzes its mitochondrial production of 1,25-dihydroxycholecalciferol (1,25-D) by as much as 30-fold. 1,25-D is the active secosteroid of the Vitamin D metabolism.
The part of the immune system which is perverted by the intracellular pathogens is the innate immune system, the last line of defense. When phagocytosis fails to kill invaders, other parts of the immune system sense there is something wrong, and they go into overdrive trying to help out. But they cannot help the phagocytes get the innate immune system functioning properly again. This is what gives rise to chronic disease. So the immune system is both non-functioning and over-functioning.
The part which is not functioning is the VDR, or Vitamin D Receptor, which is responsible for transcribing between 1000 and 27,000 genes. The VDR is blocked by the intra-phagocytic bacteria, as they need to block it from producing the body's anti-microbial peptides, which kill invading organisms. When they block the VDR they also take out many other important functions the VDR would normally perform.
1,25-dihydroxyvitamin-D (calcitriol) is a secosteroid hormone. Its most important function is to bind to a nuclear receptor called the VDR (Vitamin D Receptor) and mediate the transcription of DNA, triggered by signaling proteins, like Nuclear-Factor-kappa-B. The VDR is also expressed in over 30 different tissues throughout the body (including the nucleus of phagocytic cells of the immune system).
In the absence of Th1 inflammatory disease, 1,25-D binds to the VDR to dampen down runaway inflammation and allow the immune system to function properly. However, intraphagocytic bacteria interfere with this process causing excess 1,25-D to be produced which inhibits the immune system from killing these bacteria.
What we see as the cause of sarcoidosis and other "autoimmune" diseases is the inability of innate immunity, and more specifically, the macrophages, to complete their task of phagocytosis (digesting the pathogens). Instead, the tiny L form (CWD) bacteria are able to persist and reproduce rather than be eliminated as they normally would be in a healthy immune system response.
There are other granulomatous diseases where phagocytosis also fails to achieve its goal of eliminating the organisms. For instance, in some chronic granulomatous diseases, there are known defects in phagocytosis that lead to chronic infection with bacterial pathogens, such as Staphylococcus, Klebsiella or Pseudomonas. Tuberculosis is a granulomatous disease in which the bacteria can outpace the immune system's ability to control them through some well-studied mechanisms used by the bacteria to resist destruction by phagocytes.
In the case of L-form bacteria in the Th1 inflammatory diseases, the exact mechanism by which the tiny L-form (CWD) bacteria are able to avoid elimination by phagocytes is not known. It may relate to protective mechanisms that the bacteria possess, like biofilms, and there is evidence that it’s related to host factors like high vitamin D levels.
PPAR (Peroxisome Proliferator-Activated Receptor) gamma is a nuclear transcription factor that controls key genes involved in fatty acid metabolism and energy homeostasis.
Molecular modeling has shown that Benicar (taken at least every eight hours) up-regulates the VDR and prevents PPARgamma from binding to 1,25-D, thus reducing excess 1,25-D and allowing the immune system to function normally again.
Acute inflammation can be a good thing for tissue damage since it isolates the damaged area, promotes the mobilization of effector cells and molecules to the area that can fight infections and injury, and then promotes healing.
Chronic inflammation (that is unsuccessful in promoting healing) can be viewed in a certain sense as inappropriate and can be detrimental to the organism since it can cause damage and loss of function.
Ideally, we want an appropriate inflammatory response that kills invaders in a reasonably short time. Since the L-forms can evade elimination by living in the cells sent to kill them, a treatment is needed to overcome this very successful survival strategy. For many, this has proven to be IT.
Last updated November 4, 2013
Note: This document contains statements which represent scientific theories supported by the medical literature and molecular modeling by an independent researcher, but not yet generally accepted by the scientific community. These theories and research fit the medical model of Inflammation Therapy which has provided considerable supporting anecdotal evidence. CIR makes no claim as to the accuracy of these statements and they will be updated whenever new information becomes available.