In 1977, an article detailing the mechanisms of osteogenesis was published in the scientific journals of Ilizarov’s institute. Many of the concepts discussed in this article are still relevant to our current understanding of tissue repair following an injury. Below is a translation of the article from Russian.
UDC 611-018.4+616.71-003.93
A. M. KHELIMSKIY.
OSTEOGENIC COLONY FORMATION IN REPARATIVE REGENERATION OF BONE TISSUE
The phenomenon of bone tissue formation during cultivation of osteogenic cells (Friedenstein A. Ya., Lalykina K. S., 1973), discovered in recent years (see the article by R. Ya. Galanova et al. in this collection), served as the basis for us to interpret the pictures of reparative bone formation in a new way. This concept of osteogenesis is presented below.
Bone damage is accompanied by two processes: 1) blood containing a certain amount of colony-forming osteogenic cells constantly circulating in the blood flows into the injury zone; 2) distant and local regulators are formed in the injury zone. Let us conventionally call the first of them a pheromone (from the Latin fero to carry, tonco to persuade), the second an attractant (from the Latin attraho to attract). The pheromone, spreading through the blood or lymph through veins or lymphatic pathways, forces the precursor cells of osteogenesis to leave the bone marrow of various bones of the body into the general blood flow. The attractant remains in the area of injury and attracts colony-forming cells of osteogenesis, giving them a signal to begin column formation. Therefore, bone formation occurs precisely at the site of injury, despite the circulation of precursor cells in the general blood flow. Both the pheromone and the attractant (regardless of their structure, mono- or polycomponent nature, etc.) must first of all be products of bone tissue disintegration, since if they were of a different origin, for example, a product of the destruction of the vascular wall, blood, fibrous tissue, etc., they would not be specific to bone formation and would not attract specifically the stem cells of osteogenesis to this focus.
Thus, if, for example, we inflict a repeated injury some time after bone injury, healing will proceed faster, since the attractant in the new place will attract pre-stimulated pheromone-stimulated cells – precursors of osteogenesis. It is only necessary that the interval between the first and repeated injuries correspond to a certain “incubation period”. We believe that the time of the onset of distraction should be partly dictated by the size of this period in each specific case.
The pheromone, of course, activates column-forming cells not only in distant parts of the body, but also in the bone marrow of the damaged bone. The attractant draws them to the injury zone. The process of osteogenic column formation, the development of a clone of bone-forming cells, begins. Three stages of colony formation can be outlined: Stage 1: formation of colonies from colony-forming cells of the hematoma in places where there are suitable conditions for this; Stage 2: formation of osteogenic colonies from activated local precursor cells in the bone marrow of the damaged bone (the beginning of the endosteal reaction). At this time, there are many small “foci” (osteogenesis colonies) in the regeneration zone. What is a colony during bone formation?. This is the offspring of one stem cell, gradually passing through the stages of differentiation through fibroblasts, preosteoblasts, osteoblasts to osteocytes, and the products of their excretory function, forming the bone matrix. The center of the column is its more mature, more differentiated sections. On the periphery are younger individuals. In the bone marrow, under conditions of stable fixation, the colonies are rounded, on cortical plates or large bone fragments they are spread out in the form of plaques (the more mature part of the colony on the base of the plaque). Often the center of the colony is located near the bone fragment of the attractant localization. Stage 3: formation of colonies from colony-forming cells that have arrived through the blood and penetrate into the damage zone along the supplying bone vessels of the periosteum or endosteum. Perosteal colonies arise in places of preserved blood supply; due to mechanical reasons they also spread out on the cortical plate in the form of plaques. The endosteal regenerate is now composed of three sources: colonies that arose in the hematoma, colonies from local precursor cells; colonies from alien precursor cells of osteogenesis. All these colonies merge as they develop, the distal part of the regenerate (where colony formation usually lags behind due to blood flow conditions) merges with the proximal part. By about day 14 after osteotomy, the colony “matures”, turning into a bone focus surrounded by active osteoblasts.The diameter of the focus is 1-2 mm. The further fate of the formed bone depends on biomechanical conditions: either it will develop as a result of the activity of osteoblasts, or in the absence of load, osteocytes will begin to die, and osteoclasts will resorb the decaying bone.
Although the center of bone formation is the vessel supplier of colony-forming cells, as the colony develops, its center, where bone formation begins, seems to move away from the vessel. As the colony matures, proliferation ceases and bone is replaced, the bone again “approaches” the vessel, now directly adjacent to it. Thus, the type of osteogenesis (desmal or angiogenic) is more appropriately considered as a manifestation of the “packing density” of the vessels, and, consequently, osteogenic colonies.
With a lack of nutrition and energy, osteogenesis is distorted, the colony turns into a chondroid focus.
It is obvious that the activity of the reparative reaction depends on the volumetric level of blood flow in a given area. The more intense the blood supply, the more intensive the delivery of colony-forming cells, nutrition and energy for the colonies. Therefore, metaphyseal injuries heal faster than diaphyseal injuries. The Ilizarov method, which preserves muscle and joint function, i.e. ensures blood and lymph flow, and the
Thus, the transport of pheromone, as well as ensuring the integrity of vessels and osteogenesis colonies in the contact zone (due to stable fixation of fragments), creates optimal conditions for bone regeneration. Bone formation should be considered from this standpoint during distraction. Distraction constantly maintains the release of pheromone and attractant, i.e. constantly maintains the influx of column-forming cells into the stretch zone. The middle growth zone in the distraction regenerate is abundantly supplied with vessels. As the density increases, it moves further and further away from the ends of the fragments. Newly formed osteoid beams in the growth zone are most exposed to the action of stretching, i.e. the formation of beams is combined with their partial disintegration, disintegration of the bone matrix. The attractant is localized here, and the vessels deliver colony-forming cells here. Here the “packing density” of the vessels is high enough to form merging lace-like colonies of bone formation around them, i.e. for the manifestation of the so-called direct angiogenic osteogenesis. At the same time, endosteal and perosteal bone formation in the fragments increasingly subsides. As the experiments of A. A. Shreiner showed, an abundant vascular network develops during distraction. At first, it is located at the ends of the fragments, corresponding to the development of endosteal foci of osteogenesis. As distraction progresses, the zone of abundant blood supply shifts toward the center of the regenerate, toward its growth zone. V. G. Berko’s studies have shown that in the growth zone the number of vessels during distraction increases on average by 1 vessel per day per 1 sq. mm of section area (during femur lengthening in dogs). Accordingly, the space between the vessels decreases. The area of the functional-structural unit of bone formation decreases during distraction from 0.040 to 0.015 mm². From the 21st to 28th day of distraction, the picture corresponding to desmal osteogenesis is replaced by a picture of direct
angiogenic bone formation. These data can be compared with the observations of
K. V. Petrakova, A. A. Tolmacheva, A. Ya. Friedenstein (1963), who showed that the direction of differentiation of the osteogenic cell culture depends on the “packing density”. Thus, when growing the same number of osteogenic cells in vivo in a chamber with an area of 50 mm², reticular tissue was formed, and in a chamber with an area of 5 mm², foci of bone formation appeared.
After distraction, during the period of subsequent fixation, the stretching of the beams ceases, the production of the Pheromone and attractant ceases, the colonies mature and the growth zone is replaced by bone.
If stability is not ensured during the healing of a bone wound, the level of injury is high, there are many colonies, but they are partially destroyed, and excessive but disordered bone formation occurs.
In the places where the spokes are inserted, the pattern of bone formation is naturally similar to that observed in other areas of damage. But if the spoke is under the action of compression or distraction forces, colony formation is induced in a certain direction. Probably, such pathological processes as ossifying myositis, ossification of tendons after injury, etc., are also the result of accidental formation of an attractant in an unusual place and the occurrence of osteogenic colony formation.
As for physiological regeneration and bone remodeling, it seems to us that this is the result of activation or inactivation under the influence of overload or inactivity of osteoblasts remaining on the bone surface (endosteum, periosteum, osteon canals), and not the result of attracting circulating colony-forming cells.
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Prolotherapy is a controlled injury utilizing mechanical, osmotic, chemical stimuli.As the result Activation of Mesenchymal Stem Cells (MSCs) occurs.
Injury Signals:
When tissue sustains damage, it releases a variety of signals, including cytokines, chemokines, and growth factors. These signals serve to attract MSCs to the site of injury and activate their functions.
MSCs from surrounding tissues and the bloodstream migrate to the wound site, drawn by chemotactic factors that are released during the initial inflammatory response.
Initiation of the Healing Process:
1. Hemostasis and Inflammation:
MSCs secreting pro-inflammatory cytokines, which help recruit neutrophils and M1 macrophages to clear debris and combat potential infections.
2. Immunomodulation:
MSCs begin to modulate the immune response, decreasing the levels of activated T cells, neutrophils, and macrophages. They also guide the polarization of monocytes into pro-reparative M2 macrophages.
3. Paracrine Signaling:
MSCs release a range of growth factors and cytokines that facilitate healing. These include vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and transforming growth factor-β (TGF-β).
Control of the Healing Process:
1. Angiogenesis:
MSCs promote the formation of new blood vessels by secreting pro-angiogenic factors.
2. Cell Proliferation and Migration:
MSCs stimulate the proliferation and migration of skin cells, such as fibroblasts and keratinocytes.
3. Extracellular Matrix (ECM) Regulation:
MSCs participate in production and remodeling of the ECM by releasing matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). They also promote collagen and elastin production by fibroblasts.
4. Re-epithelialization:
MSCs enhance the migration and proliferation of keratinocytes, which is essential for wound closure.
5. Granulation Tissue Formation:
MSCs contribute to the development of granulation tissue, characterized by a rich collagen III matrix.
6. Anti-fibrotic Activity:
MSCs help prevent excessive scarring by maintaining a balance between TGF-β1 and TGF-β3.
7. Resolution of Inflammation:
As healing progresses, MSCs continue to modulate the inflammatory response, facilitating a transition from pro-inflammatory to anti-inflammatory conditions.
Throughout the healing process, MSCs demonstrate plasticity, adapting their functions to the changing needs of the wound environment. They orchestrate the complex interplay between various cell types and signaling molecules, promoting a regenerative rather than a fibrotic healing response
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Connective tissue healing. Review literature by Jon Trister MD
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Connective tissue healing s a systematic process that can be categorized into four overlapping stages: hemostasis, inflammation, proliferation, and remodeling. Each stage is marked by distinct cellular activities and accompanying symptoms.
1. Hemostasis (Immediate to 1-2 days)
This stage serves as the body’s immediate response to injury, aimed at halting bleeding.
Key processes: Blood vessels constrict , and platelets aggregate to form a blood clot that seals the wound. This clot acts as a temporary matrix for the healing process.
Symptoms: While minimal symptoms may be present, slight swelling or redness at the injury site may occur as clotting commences.
Key Cells: Platelets, the principal cells in this phase, are small, disc-shaped fragments that adhere to damaged endothelium, releasing factors like fibrinogen and von Willebrand factor to form a clot (thrombus). Their primary function is to prevent further bleeding and provide a scaffold for subsequent healing stages.
Mesenchymal stem cells help by secreting factors that modulate the inflammatory response. They release pro-inflammatory cytokines that recruit immune cells like neutrophils and macrophages to the wound site, which are essential for clearing debris and preventing infection. MSCs also help form a stable clot by interacting with platelets and fibrin mesh.
2. Inflammation (1-7 days) Inflammation acts as the body’s defense mechanism, cleaning the wound and preparing for tissue repair.
Key processes: White blood cells, such as neutrophils and macrophages, migrate to the injury site to eliminate debris and bacteria. This phase also sees vasodilation, which enhances blood flow to the area.
Symptoms: Expect swelling, redness, warmth, pain, and occasionally a loss of function. These symptoms arise from increased blood flow and immune responses in the affected area.
Key Cells:Neutrophils:Multi-lobed, granular white blood cells that arrive at the injury site within hours, engulfing pathogens and debris through phagocytosis.
Macrophages: Large, amoeboid cells with kidney-shaped nuclei that arrive later; they phagocytose dead cells and release cytokines to attract more immune cells and encourage tissue repair.
Mast Cells: Containing granules rich in histamine, these cells promote vasodilation and increase vascular permeability, facilitating immune cell influx.
Mesenchymal stem cells exert immunomodulatory effects. They reduce excessive inflammation by shifting macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type. This polarization helps clear apoptotic cells and debris while promoting tissue repair. MSCs also secrete anti-inflammatory cytokines like IL-10, which further dampen the inflammatory response.
3.Proliferation (3 days to 3 weeks)
This stage focuses on rebuilding damaged tissue.
Key processes: Fibroblasts generate collagen and extracellular matrix, forming granulation tissue. Angiogenesis occurs as new blood vessels form, and myofibroblasts contract the wound, pulling its edges together.
Symptoms: The injury site may appear pink or red due to new blood vessel formation. It may feel tender but less painful than during inflammation, and some itching may be experienced as new tissue develops.
Key Cells: Fibroblasts, myofibroblasts, endothelial cells, and keratinocytes.
Morphology:
Fibroblasts: Spindle-shaped cells synthesizing collagen and extracellular matrix (ECM). They become activated during this phase, exhibiting enlarged nuclei and abundant rough endoplasmic reticulum for ECM production.
Myofibroblasts: Derived from fibroblasts, these cells possess characteristics of both fibroblasts and smooth muscle cells, including actin filaments that aid in wound contraction.
Endothelial Cells: Flat, elongated cells that proliferate to form new blood vessels (angiogenesis), ensuring a sufficient oxygen supply to healing tissue.
Keratinocytes: Epithelial cells that migrate from the wound edges to re-establish the epidermis, appearing flattened as they spread across the wound bed.
Mesenchymal stem cells are involved in tissue regeneration. They promote the proliferation and migration of fibroblasts, keratinocytes, and endothelial cells, which are essential for angiogenesis, collagen deposition, and re-epithelialization of the wound. MSCs also stimulate granulation tissue formation, which is important for filling the wound bed with new extracellular matrix .
4. Remodeling (3 weeks to 1 year or more)
These stage involves strengthening and reorganizing newly formed tissue.
Key processes:Collagen fibers transition from disorganized type III collagen to the stronger type I collagen. The tissue gradually regains strength, although it will never be as strong as uninjured tissue.
Symptoms: There is typically reduced swelling and pain, but the skin or connective tissue may feel tight or stiff as scar tissue develops. Over time, scars may become less noticeable but will remain weaker than the original tissue.
Key Cells: Myofibroblasts, fibroblasts, and apoptotic immune cells.
Morphology:
Myofibroblasts: Continue to contract the wound while depositing type I collagen. Their actin filaments are prominent in this stage, enhancing ECM strength.
Fibroblasts: Remodel the collagen matrix by converting type III collagen to stronger type I collagen. They become less active as remodeling progresses, but are crucial for maintaining tissue integrity.
Many immune cells undergo apoptosis (programmed cell death) once their role in healing is complete, resulting in decreased cellularity at the injury site.
Mesenchymal stem cells contribute to tissue remodeling by regulating ECM turnover through the secretion of matrix metalloproteinases and their inhibitors. This process helps replace disorganized collagen III with stronger collagen I, reducing scarring and improving tissue strength. Additionally, MSCs help prevent fibrosis by maintaining a balance between different growth factors like TGF-β1 and TGF-β3.
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involves both intracellular and extracellular stages. It is essential for the formation of collagen, the most abundant protein in the body, which provides structural support to various tissues, including skin, bones, tendons, and cartilage. Here are the key steps involved in collagen synthesis:
- Transcription and Translation
• Transcription: The process begins inside the cell with the transcription of collagen genes into messenger RNA (mRNA). This occurs in the nucleus of fibroblasts (specialized cells responsible for collagen production).
• Translation: The mRNA is transported to ribosomes on the rough endoplasmic reticulum , where it is translated into a polypeptide chain known as preprocollagen. - Hydroxylation
• Hydroxylation of Proline and Lysine: The preprocollagen undergoes post-translational modifications in the RER. Specifically, certain proline and lysine residues are hydroxylated by enzymes (prolyl and lysyl hydroxylases) to form hydroxyproline and hydroxylysine. This step requires vitamin C as a cofactor.
• This hydroxylation is crucial for stabilizing the collagen triple helix structure. - Glycosylation
• Glycosylation of Hydroxylysine: After hydroxylation, some hydroxylysine residues are glycosylated with glucose or galactose sugars. This modification helps in the proper folding and assembly of procollagen. - Formation of Procollagen
• Triple Helix Formation: Three alpha chains (two alpha-1 chains and one alpha-2 chain) twist together into a triple helix structure, forming procollagen. This helical structure is stabilized by hydrogen and disulfide bonds. - Transport to Golgi Apparatus
• The procollagen molecules are transported from the RER to the Golgi apparatus, where they undergo further modifications and are packaged into vesicles for secretion. - Exocytosis
• Secretion into Extracellular Space: Procollagen is secreted from the cell through exocytosis into the extracellular matrix (ECM). - Cleavage of Propeptides
• Formation of Tropocollagen: Once outside the cell, specific enzymes called collagen peptidases cleave off the terminal propeptides from procollagen, converting it into tropocollagen, which is now capable of forming fibrils. - Cross-Linking and Fibril Formation • Cross-Linking by Lysyl Oxidase: Tropocollagen molecules spontaneously assemble into collagen fibrils. The enzyme lysyl oxidase (which requires copper as a cofactor) catalyzes covalent cross-linking between lysine residues, strengthening these fibrils. • These fibrils then aggregate to form larger collagen fibers, which provide tensile strength to tissues like skin, tendons, and bones. Summary of Key Steps
- Transcription and translation of preprocollagen.
- Hydroxylation of proline and lysine residues (vitamin C-dependent).
- Glycosylation of hydroxylysine residues.
- Formation of procollagen triple helix.
- Transport through Golgi apparatus.
- Secretion into extracellular space.
- Cleavage of propeptides to form tropocollagen.
- Cross-linking by lysyl oxidase to form collagen fibrils.
This intricate process ensures that collagen maintains its structural integrity, but disruptions at any step can lead to disorders such as scurvy (vitamin C deficiency), Ehlers-Danlos syndrome (defective cross-linking), or osteogenesis imperfecta (defective triple helix formation).
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Vasa Vasorum
- Definition: Small blood vessels that supply the walls of larger arteries and veins.
- Function: Provide nourishment to the outer layers (tunica externa) of large blood vessels, as diffusion from the lumen is insufficient for thick vessel walls.
Vasa Nervorum
- Definition: Small arteries that supply blood to peripheral nerves.
- Function: Provide essential nutrients to the interior parts of nerves and their coverings, crucial for nerve function and survival.
Nervi Vasorum
- Definition: Nerves that innervate blood vessels.
- Function: Control vasodilation and vasoconstriction, regulating blood flow and pressure.
Nervi Nervorum
- Definition: Nerves that innervate the connective tissue sheaths of peripheral nerves.
- Function: Involved in the sensation and regulation of pain within nerve sheaths, though not directly covered in the search results, they are known for their role in nerve health and pain perception.
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The immune system is comprised of two main subsystems: innate immunity and adaptive immunity. These systems work collaboratively to protect the body from pathogens and maintain overall health.
Innate Immunity
Innate immunity serves as the body’s first line of defense against pathogens. This response is non-specific, meaning it does not differentiate between different types of pathogens. Key characteristics of innate immunity include:
– Immediate Response: It acts swiftly, combating infections within minutes or hours.
– Non-Specific Defense: It targets all pathogens in a similar manner, without specificity.
– No Immunological Memory: Unlike adaptive immunity, innate immunity does not retain a memory of previous encounters with pathogens.
The components of the innate immune system include physical barriers like skin and mucous membranes, chemical barriers such as stomach acid, and cellular defenses, including phagocytes like macrophages and neutrophils. Innate immunity also encompasses processes like inflammation, which helps recruit immune cells to sites of infection.
The innate immune system consists of various cell types, each fulfilling specific roles that form the body’s first line of defense against pathogens. Below are the main cells involved in innate immunity, along with their respective functions and distinguishing characteristics.
Cells of the Innate Immune System
Phagocytes: This category includes cells like macrophages and neutrophils, which are responsible for engulfing and digesting pathogens through a process known as phagocytosis. They serve as “security guards,” patrolling the body to identify and eliminate potential threats such as bacteria and viruses.
Macrophages: Originating from monocytes, macrophages are long-lived cells located in nearly all tissues. They play a vital role in phagocytosis and secrete cytokines to recruit additional immune cells, thereby promoting inflammation. Macrophages are also capable of presenting antigens to activate the adaptive immune system.
Neutrophils: As the most abundant white blood cells in the innate immune system, neutrophils are short-lived but highly effective in ingesting and destroying bacteria and fungi using toxic granules.
Dendritic Cells: These cells serve as a crucial link between innate and adaptive immunity. They capture antigens and present them to T cells, thereby initiating an adaptive immune response. Dendritic cells are essential for processing antigens from a wide variety of pathogens.
Natural Killer (NK) Cells: NK cells target and destroy infected or cancerous cells by recognizing abnormal surface markers. They release cytotoxins that kill these compromised cells, providing a rapid response against viral infections and tumor formation.
Granulocytes: This group comprises basophils, eosinophils, and mast cells. Basophils and eosinophils play roles in combating parasites and mediating allergic reactions, while mast cells release histamine and other chemicals during inflammatory responses.
Functions and Differences
– Phagocytosis: Macrophages and neutrophils primarily focus on engulfing pathogens to neutralize them.
– Inflammation: Both macrophages and mast cells release cytokines that promote inflammation, helping to recruit additional immune cells to the site of infection.
– Antigen Presentation: Dendritic cells specialize in presenting antigens to T cells, thereby linking innate and adaptive immunity.
– Cytotoxicity: NK cells can directly kill infected or abnormal cells without prior sensitization.
Each cell type significantly contributes to recognizing and responding to pathogens, enhancing the overall efficacy of the innate immune response. While the innate immune system acts quickly and non-specifically, it provides immediate defense as the adaptive immune system prepares a more targeted response.
Adaptive Immunity
Adaptive immunity, also known as acquired immunity, develops over time and provides a specific response to pathogens. Its key features are:
– Specificity: It targets specific antigens found on pathogens.
– Memory: Adaptive immunity retains information about past infections, enabling a more rapid and effective response upon re-exposure to the same pathogen.
– Delayed Response: This type of immunity takes longer to activate compared to innate immunity, often requiring days or weeks to mount a full response.
Adaptive immunity involves specialized cells, such as B cells and T cells. B cells produce antibodies that neutralize pathogens, while T cells can directly eliminate infected cells or assist in activating other immune cells. This system is responsible for the long-lasting protection conferred by vaccines and previous infections.
The adaptive immune system is primarily composed of two types of lymphocytes: B cells and T cells. These cells play crucial roles in recognizing and responding to specific pathogens, and they have distinct functions and characteristics.
B Cells
Functions:
- Antibody Production: B cells are responsible for producing antibodies, which are proteins that bind to specific antigens on pathogens, marking them for destruction or neutralization.
- Humoral Immunity: B cells mediate humoral immunity, which involves the secretion of antibodies into bodily fluids to combat extracellular pathogens.
- Antigen Presentation: B cells can present antigens to T cells, aiding in the activation of the adaptive immune response.
Characteristics:
- Maturation: B cells mature in the bone marrow.
- Receptors: They possess B cell receptors (BCRs) on their surface, which are specific to particular antigens.
- Activation: Upon encountering their specific antigen, B cells can differentiate into plasma cells that produce antibodies or memory B cells that provide long-term immunity.
T Cells
Functions:
- Helper T Cells (Th): These cells assist other immune cells by releasing cytokines that enhance the immune response. They help activate B cells and cytotoxic T cells.
- Cytotoxic T Cells (Tc): These cells directly kill infected or cancerous cells by recognizing antigens presented on their surface.
- Memory T Cells: After an infection is cleared, some T cells become memory T cells, providing a faster response if the same antigen is encountered again.
Characteristics:
- Maturation: T cells originate in the bone marrow but mature in the thymus.
- Receptors: They have T cell receptors (TCRs) that recognize antigens presented by major histocompatibility complex (MHC) molecules on other cells.
- Types: There are several types of T cells, including helper T cells, cytotoxic T cells, and regulatory T cells that help maintain immune tolerance.
Differences Between B Cells and T Cells
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Feature
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B Cells
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T Cells
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|
Origin
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Bone marrow
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Bone marrow
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Maturation Site
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Bone marrow
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Thymus
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Main Function
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Produce antibodies
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Kill infected/cancerous cells; assist other immune responses
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|
Immunity Type
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Humoral immunity
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Cell-mediated immunity
|
|
Receptor Type
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B cell receptor (BCR)
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T cell receptor (TCR)
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|
Antigen Recognition
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Recognize free antigens
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Recognize processed antigens presented by MHC
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|
Subtypes
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Plasma cells, Memory B cells
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Helper T cells, Cytotoxic T cells, Memory T cells
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Both B and T cells are essential for the adaptive immune response, providing specificity and memory that enhance the body’s ability to fight infections more effectively upon re-exposure to pathogens.
The adaptive immune system is primarily composed of two types of lymphocytes: B cells and T cells. These cells play crucial roles in recognizing and responding to specific pathogens, and they have distinct functions and characteristics.
B Cells
Functions:
- Antibody Production: B cells are responsible for producing antibodies, which are proteins that bind to specific antigens on pathogens, marking them for destruction or neutralization.
- Humoral Immunity: B cells mediate humoral immunity, which involves the secretion of antibodies into bodily fluids to combat extracellular pathogens.
- Antigen Presentation: B cells can present antigens to T cells, aiding in the activation of the adaptive immune response.
Characteristics:
- Maturation: B cells mature in the bone marrow.
- Receptors: They possess B cell receptors (BCRs) on their surface, which are specific to particular antigens.
- Activation: Upon encountering their specific antigen, B cells can differentiate into plasma cells that produce antibodies or memory B cells that provide long-term immunity.
T Cells
Functions:
- Helper T Cells (Th): These cells assist other immune cells by releasing cytokines that enhance the immune response. They help activate B cells and cytotoxic T cells.
- Cytotoxic T Cells (Tc): These cells directly kill infected or cancerous cells by recognizing antigens presented on their surface.
- Memory T Cells: After an infection is cleared, some T cells become memory T cells, providing a faster response if the same antigen is encountered again.
Characteristics:
- Maturation: T cells originate in the bone marrow but mature in the thymus.
- Receptors: They have T cell receptors (TCRs) that recognize antigens presented by major histocompatibility complex (MHC) molecules on other cells.
- Types: There are several types of T cells, including helper T cells, cytotoxic T cells, and regulatory T cells that help maintain immune tolerance.
Differences Between B Cells and T Cells
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Feature
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B Cells
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T Cells
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|
Origin
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Bone marrow
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Bone marrow
|
|
Maturation Site
|
Bone marrow
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Thymus
|
|
Main Function
|
Produce antibodies
|
Kill infected/cancerous cells; assist other immune responses
|
|
Immunity Type
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Humoral immunity
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Cell-mediated immunity
|
|
Receptor Type
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B cell receptor (BCR)
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T cell receptor (TCR)
|
|
Antigen Recognition
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Recognize free antigens
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Recognize processed antigens presented by MHC
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|
Subtypes
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Plasma cells, Memory B cells
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Helper T cells, Cytotoxic T cells, Memory T cells
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Both B and T cells are essential for the adaptive immune response, providing specificity and memory that enhance the body’s ability to fight infections more effectively upon re-exposure to pathogens.
T-helper (Th) cells are a subset of CD4+ T cells that play crucial roles in orchestrating the immune response. The Th1, Th2, and Th17 subsets are particularly important, each with distinct functions and cytokine profiles.
Th1 Cells
Functions:
- Intracellular Pathogen Defense: Th1 cells are primarily involved in defending against intracellular pathogens like viruses and certain bacteria. They activate macrophages and enhance their ability to kill ingested microbes.
- Cytokine Production: Th1 cells produce cytokines such as interferon-gamma (IFN-γ), which is crucial for macrophage activation and enhancing the cytotoxic activity of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs).
Characteristics:
- Activation: Th1 differentiation is driven by cytokines like IL-12 and IFN-γ.
- Role in Disease: An excessive Th1 response can contribute to autoimmune diseases by promoting inflammation.
Th2 Cells
Functions:
- Extracellular Pathogen Defense: Th2 cells are essential for combating extracellular parasites such as helminths. They promote the production of antibodies by B cells.
- Cytokine Production: Th2 cells secrete cytokines including IL-4, IL-5, IL-10, and IL-13, which facilitate B cell class switching to IgE and activate eosinophils and mast cells.
Characteristics:
- Activation: Th2 differentiation is induced by cytokines like IL-4.
- Role in Disease: Overactive Th2 responses are associated with allergies, asthma, and other atopic conditions.
Th17 Cells
Functions:
- Defense Against Extracellular Pathogens: Th17 cells protect against extracellular bacteria and fungi, particularly at mucosal surfaces.
- Cytokine Production: They produce pro-inflammatory cytokines such as IL-17A, IL-17F, and IL-22, which recruit neutrophils and enhance barrier integrity.
Characteristics:
- Activation: Th17 differentiation requires cytokines like TGF-β, IL-6, and IL-23.
- Role in Disease: While critical for host defense, dysregulated Th17 activity is implicated in autoimmune diseases like psoriasis and rheumatoid arthritis.
Comparison of Th1/Th17 vs. Th2
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Feature
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Th1/Th17
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Th2
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Primary Targets
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Intracellular pathogens (Th1); Extracellular bacteria/fungi (Th17)
|
Extracellular parasites
|
|
Key Cytokines
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IFN-γ (Th1), IL-17 (Th17)
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IL-4, IL-5, IL-13
|
|
Immune Response
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Cell-mediated immunity
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Humoral immunity
|
|
Associated Diseases
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Autoimmune diseases (e.g., MS for Th1; arthritis for Th17)
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Allergies, asthma
|
The balance between these subsets is crucial for maintaining immune homeostasis. Imbalances can lead to various immune-related disorders, highlighting the importance of understanding their distinct roles in immunity.
Vitamin D plays a crucial role in the immune system, impacting both innate and adaptive immunity. Here’s an overview of vitamin D sources, metabolites, activation, and its function in relation to the immune system:
Sources of Vitamin D
- Sunlight: The primary source of vitamin D is sunlight. When skin is exposed to UVB rays, it synthesizes vitamin D3 (cholecalciferol).
- Food: Dietary sources include oily fish (e.g., salmon, sardines), egg yolks, liver, and fortified foods like milk and cereals.
- Supplements: Vitamin D supplements are available in forms such as vitamin D2 (ergocalciferol) and vitamin D3.
Metabolites and Activation
Vitamin D undergoes several transformations to become active:
- Synthesis: In the skin, 7-dehydrocholesterol is converted to vitamin D3 upon UVB exposure.
- Liver Conversion: Vitamin D3 is hydroxylated in the liver to form 25-hydroxyvitamin D (25(OH)D), the main circulating form and a marker for vitamin D status.
- Kidney Activation: 25(OH)D is further hydroxylated in the kidneys to produce 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form that exerts biological effects.
Function in the Immune System
Vitamin D influences both innate and adaptive immune responses:
- Innate Immunity:
- Modulation of Immune Cells: Vitamin D binds to receptors on immune cells like macrophages and dendritic cells, enhancing their pathogen-fighting capabilities.
- Antimicrobial Peptides: It stimulates the production of antimicrobial peptides such as cathelicidins and defensins, which have antiviral properties.
- Adaptive Immunity:
- T Cell Regulation: Vitamin D modulates T cell responses by inhibiting Th1 and Th17 cell proliferation while promoting regulatory T cells (Tregs), which help maintain immune tolerance.
- B Cell Function: It can reduce the production of autoantibodies by B cells, potentially ameliorating autoimmune conditions.
Impact on Health
- Autoimmune Diseases: Vitamin D deficiency is linked to increased risk of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Supplementation may help modulate disease activity.
- Infections: Adequate vitamin D levels are associated with reduced susceptibility to infections like respiratory tract infections.
The conversion of 25-hydroxyvitamin D (25(OH)D) to its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), and its subsequent inactivation involves specific cytochrome P450 enzymes.
Activation of Vitamin D
- CYP27B1: This enzyme, also known as 25-hydroxyvitamin D-1α-hydroxylase, is responsible for converting 25(OH)D to the active form 1,25(OH)2D (calcitriol). This conversion primarily occurs in the kidneys but can also take place in other tissues like the placenta and immune cells.
Inactivation of Vitamin D
- CYP24A1: Known as 25-hydroxyvitamin D3-24-hydroxylase, CYP24A1 is involved in the catabolism of vitamin D. It converts both 25(OH)D and 1,25(OH)2D into inactive forms by hydroxylating them at the 24-position. This process is crucial for regulating and maintaining appropriate levels of active vitamin D in the body.
- CYP3A4: Although primarily recognized for its role in drug metabolism, CYP3A4 can also participate in the catabolism of vitamin D by hydroxylating it into less active forms.
These enzymes ensure a balance between the activation and inactivation of vitamin D, which is essential for maintaining calcium homeostasis and supporting various physiological processes, including immune function.
The activation of CYP27B1, the enzyme responsible for converting 25-hydroxyvitamin D (25(OH)D) to its active form, 1,25-dihydroxyvitamin D (1,25(OH)2D), is regulated by several factors:
- Parathyroid Hormone (PTH): PTH is a primary activator of CYP27B1. It increases the expression of this enzyme, promoting the conversion of 25(OH)D to 1,25(OH)2D. This process is crucial for maintaining calcium homeostasis, as 1,25(OH)2D enhances intestinal calcium absorption.
- Fibroblast Growth Factor 23 (FGF23): While FGF23 primarily acts to decrease the synthesis of 1,25(OH)2D by reducing CYP27B1 activity, it plays a role in the overall regulation of phosphate and vitamin D metabolism.
- Calcium and Phosphate Levels: Changes in serum calcium and phosphate levels can influence CYP27B1 activity. Low calcium levels typically stimulate PTH release, which in turn activates CYP27B1.
- Feedback Regulation by 1,25(OH)2D: The active form of vitamin D itself can downregulate CYP27B1 expression as part of a feedback loop to prevent excessive production of 1,25(OH)2D.
- Cytokines: In extrarenal tissues, cytokines such as interferon-gamma (IFN-γ) can upregulate CYP27B1 expression, particularly in immune cells like macrophages during inflammatory responses.
6.Infections can upregulate the expression of CYP27B1. The enzyme CYP27B1, which is responsible for converting inactive vitamin D into its active form, is expressed in various immune cells, including macrophages and dendritic cells. This expression is regulated by immune inputs such as interferon-gamma (IFN-γ), a cytokine secreted by T cells, and agonists of pattern recognition receptors (PRRs) like Toll-like receptors (TLRs).PRR recognizes PAMP on bacterias
When these immune pathways are activated, such as during an infection, there is an increase in CYP27B1 expression. For example, stimulation of macrophages with TLR ligands has been shown to induce CYP27B1 expression and enhance the production of active vitamin D (1,25-dihydroxyvitamin D) from its precursor. This process plays a significant role in the immune response by boosting antimicrobial activities and enhancing innate immune responses.
Studies have shown that injury or microbial stimulation can lead to increased CYP27B1 expression in keratinocytes through the activation of TLR2. This suggests that the upregulation of CYP27B1 during infections is part of a broader immune response mechanism aimed at enhancing the body’s ability to fight off pathogens.
These regulatory mechanisms ensure that the production of active vitamin D is tightly controlled, balancing its roles in calcium homeostasis and immune function.
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Prolotherapy is a controlled injury to the connective tissues of joints and their capsules, tendons, ligaments and cartilages. Injury triggers the activation of mesenchymal stem cells (MSCs) within treated areas. When an injury occurs, it creates a localized microenvironment rich in cytokines and growth factors that attract and activate various stem cells, including MSCs. This activation is part of a complex response to tissue damage, with MSCs playing a crucial role in modulating inflammation and promoting tissue repair.
MSCs have the ability to sense and respond to signals emitted by injured tissues. For instance, they can be activated by mitochondria released from damaged cells, which serve as danger signals. This interaction prompts MSCs to enhance their cytoprotective functions, including anti-apoptotic and anti-inflammatory activities. Additionally, MSCs can modulate immune responses by influencing macrophage polarization, which is essential for controlling inflammation and fostering tissue regeneration after injuries, such as spinal cord damage.In summary, injury activates mesenchymal stem cells, which contribute to tissue repair and regeneration through various mechanisms, including immune modulation and direct interactions with damaged cells.
Mesenchymal stem cells (MSCs) support the regeneration of connective tissue through several mechanisms:
1. Paracrine Signaling: MSCs secrete a range of growth factors, cytokines, and hormones that impact their surrounding environment. These secreted factors promote cell survival, reduce inflammation, and stimulate the proliferation and differentiation of resident cells in the damaged tissue.
2. Immunomodulation: MSCs have immunomodulatory properties that help create a regenerative microenvironment. They can suppress immune responses, thereby reducing inflammation and enhancing tissue repair and regeneration.
3. Angiogenesis Promotion: MSCs facilitate the formation of new blood vessels (angiogenesis) by releasing factors that stimulate endothelial cells. This process is vital for supplying nutrients and oxygen to regenerating tissues.
4. Extracellular Matrix Remodeling: MSCs assist in remodeling the extracellular matrix by regulating collagen synthesis and deposition, which helps restore the structural integrity of connective tissues.
5. Direct Differentiation: Although not their primary function, MSCs can differentiate into various cell types, including osteoblasts, chondrocytes, and adipocytes, thereby contributing directly to tissue regeneration when necessary.
These combined actions establish MSCs as a powerful resource in regenerative medicine for repairing and regenerating connective tissues.
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The Myers’ Cocktail is an intravenous vitamin therapy designed to deliver a high concentration of vitamins and minerals directly into the bloodstream. It was developed by Dr. John Myers in the 1970s and is widely used in complementary and alternative medicine.
Composition and Benefits
The standard formulation of the Myers’ Cocktail typically includes:
– Vitamins: B-Complex vitamins, Vitamin B12, and Vitamin C
– Minerals : Magnesium and Calcium
– Other Components: Sometimes includes zinc and glutathione, depending on the specific formulation.
The cocktail is believed to offer several health benefits, including:
– Boosting the immune system
– Increasing energy levels
– Reducing fatigue
– Improving overall health and well-being
– Detoxifying the body
– Reducing stress, anxiety, and depression
It is also used to address various health conditions such as asthma, migraines, chronic fatigue syndrome, fibromyalgia, and upper respiratory tract infections.
Administration
The Myers’ Cocktail is administered intravenously, allowing the nutrients to bypass the digestive system and enter the bloodstream directly. This method ensures rapid absorption and higher bioavailability of the nutrients compared to oral supplements.
When administered correctly, the Myers’ Cocktail is generally considered safe, with serious side effects being rare. However, potential temporary side effects can occur, and patients are advised to consult with Doctor or NP to assess any risks, especially if they have underlying health conditions.
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Orange Peel Tea for Immune Support
During these uncertain times, supporting your immune system and the microbiome is important. You can drink this tea throughout the day and swish it around your mouth (unsweetened) to support the oral and gut microbiome.
Ingredients:
Orange or any citrus peel (from 4-5 fruits)1/4 Onion1 inch Ginger2-3 Sprigs of Rosemary2 tsp Whole Cloves2-3 Star Anise1-2 tbs Fennel seeds
8-10 cups water. Bring to a boil & simmer for 20 minutes (or up to an hour)
Keep in mind that you don’t have to have every single ingredient. There is no way to do this wrong. A simple tea of citrus peel is helpful. The other ingredients can be rotated. The goal is to use what you have on hand and get lots of polyphenols from these plants. Boiling these plants in water helps get the nutrients out. You can use a vegetable peeler to peel the citrus and save the peels in a bowl as you go in your fridge. Once you have enough, you can make tea. If you are having digestive issues, prioritize the ginger and fennel after the citrus peel. The onion provides quercetin, a flavonoid, useful for immune support, and is very antimicrobial. You don’t taste it in the tea, but it provides benefits. The spices all function to support the gut flora. Star anise contains shikimic acid and is used as a base material for the production of Tamiflu.
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