Brief review of Immune system (Part1)

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

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

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

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:

1. Synthesis: In the skin, 7-dehydrocholesterol is converted to vitamin D3 upon UVB exposure.
2. 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.
3. 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:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

Additionally, 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.