WEEK 3: Childhood Immune Deficiencies Flashcards
Innate immunity is the first line of defense.
It has the same response even when it is not the first time the pathogen invades the body.
Why is it like that?
It does not form memory.
Describe how the following act as part of innate immunity.
Epithelium/ skin/ cilia
- Epithelium:
Barrier Function: Epithelial tissues form a protective barrier that covers the surfaces of the body, both external (e.g., skin) and internal (e.g., lining of the respiratory and gastrointestinal tracts).
Preventing Pathogen Entry: The tight junctions between epithelial cells create a physical barrier that prevents pathogens, such as bacteria and viruses, from easily entering underlying tissues. This barrier helps to protect the body’s internal environment from external threats.
- Skin:
*Physical Barrier: The skin is the body’s largest organ and serves as a physical barrier that protects against the entry of pathogens. The outermost layer of the skin, the epidermis, is composed of tightly packed epithelial cells that are difficult for pathogens to penetrate.
*Chemical Defenses: The skin produces various antimicrobial substances, such as sweat and sebum, which create an acidic environment that inhibits the growth of many microorganisms. Additionally, the presence of normal skin flora helps to competitively exclude harmful pathogens.
- Cilia:
Respiratory Tract Defense:
Cilia are hair-like structures found on the surface of certain epithelial cells, particularly in the respiratory tract. In the airways, cilia continuously beat in coordinated waves, directing mucus and trapped particles away from the lungs toward the throat.
Mucociliary Clearance: Cilia, along with mucus produced by goblet cells, form the mucociliary escalator, a mechanism that helps remove inhaled particles and pathogens from the respiratory tract. This process prevents the entry of microbes into the lower respiratory system.
Describe how the following act as part of the innate immunity.
Lysozyme/ lactoferrin/ interferons/ TNF
- Lysozyme:
Enzymatic Activity:
Lysozyme is an enzyme with antimicrobial properties that can break down the cell walls of certain bacteria. It is found in various secretions, including tears, saliva, and mucus.
Bacterial Defense:
By cleaving the peptidoglycan layer in bacterial cell walls, lysozyme weakens the structural integrity of bacteria, making them more susceptible to other immune defenses and reducing their ability to cause infection.
- Lactoferrin:
Iron Sequestration:
Lactoferrin is a glycoprotein that binds to iron, an essential nutrient for the growth of many bacteria and fungi. By sequestering iron, lactoferrin restricts the availability of this important element to pathogens.
Antimicrobial Activity:
Lactoferrin also exhibits direct antimicrobial activity by disrupting the integrity of bacterial and fungal cell membranes, helping to prevent their colonization and proliferation.
- Interferons:
Antiviral Defense:
Interferons are signaling proteins released by cells in response to viral infections. They play a crucial role in limiting the spread of viruses by inhibiting viral replication in infected cells and enhancing the immune response.
Induction of Antiviral State:
Interferons induce an antiviral state in neighboring cells, making them more resistant to viral infection. This process involves the activation of various antiviral pathways within the cells.
- Tumor Necrosis Factor (TNF):
Inflammation:
TNF is a pro-inflammatory cytokine that plays a central role in the initiation of inflammation. It is released by immune cells in response to infection, injury, or other stimuli.
Host Defense:
TNF helps orchestrate the immune response by promoting the recruitment and activation of immune cells to the site of infection. It also plays a role in activating other components of the immune system, contributing to the elimination of pathogens.
Describe how the following are involved in innate immunity.
Cells:
1. Phagocytic cells:
*Neutrophils
*Monocytes/ macrophages e.g. Langerhans’s cells/ Kupffer cells/ Mesangial cells/ Microglial cells/ Histiocytes.
- NK cells
- Neutrophils:
Function: Neutrophils are the most abundant type of white blood cells and play a primary role in the early stages of the immune response.
Phagocytosis: Neutrophils are highly efficient phagocytes that can quickly migrate to sites of infection or tissue damage. They engulf and digest pathogens, particularly bacteria and fungi.
Chemotaxis: Neutrophils are attracted to sites of infection by chemical signals, a process known as chemotaxis. This allows them to navigate through tissues to reach the source of the infection.
- Monocytes/Macrophages:
Monocytes: Monocytes are circulating white blood cells that can differentiate into macrophages. They are involved in the initial response to infection.
Macrophages: Macrophages are found in tissues throughout the body, where they serve as long-lived immune cells. They are especially prevalent in organs like the spleen, liver, and lungs.
Phagocytosis: Macrophages are highly effective phagocytes that engulf a wide range of pathogens, cellular debris, and foreign particles. They also play a role in removing dead or damaged cells.
Antigen Presentation: After phagocytosis, macrophages process and present antigens from the engulfed material to other immune cells, helping to initiate an adaptive immune response.
Both neutrophils and monocytes/macrophages contribute to the innate immune response in several ways:
*Inflammation: Phagocytic cells release various inflammatory mediators, such as cytokines, to recruit other immune cells and enhance the overall immune response.
*Microbial Killing: Once inside the phagocyte, pathogens are exposed to various antimicrobial mechanisms, including reactive oxygen species, lysosomal enzymes, and other toxic molecules, leading to their destruction.
*Tissue Repair: Phagocytic cells play a role in tissue repair and remodeling after the resolution of an infection or injury.
Describe how the following is involved in innate immunity.
*Normal flora
- Colonization Resistance:
Barrier Effect: The presence of normal flora creates a barrier that helps prevent the colonization of pathogenic microorganisms. By occupying ecological niches, commensal bacteria can limit the space available for potentially harmful bacteria to establish themselves.
- Competition for Resources:
Nutrient Competition: Commensal microorganisms compete with pathogens for essential nutrients. This competition can limit the growth and survival of potential invaders, contributing to the overall defense against infections.
- Production of Antimicrobial Substances:
Bacteriocins: Some normal flora bacteria produce substances known as bacteriocins, which have antimicrobial properties. Bacteriocins can inhibit the growth of closely related bacteria and provide a competitive advantage to the producing strains.
- Modulation of the Immune System:
Immunomodulation: Normal flora influences the development and regulation of the immune system. Interactions between the microbiota and the immune system help shape the immune response, promoting a balanced and appropriate reaction to potential threats.
Maintenance of Epithelial Integrity:
- Barrier Function: Commensal microorganisms contribute to the maintenance of the integrity of epithelial surfaces. They help strengthen the physical barrier provided by the epithelial cells, reducing the risk of pathogens crossing these barriers and entering the bloodstream.
Induction of Tolerance: - Immune Tolerance: The presence of normal flora helps induce immune tolerance, preventing unnecessary immune responses to harmless antigens. This is crucial for preventing chronic inflammation and autoimmune reactions.
- Educating the Immune System:
Immune System Training: Normal flora educates the immune system, particularly in the gut-associated lymphoid tissue (GALT), helping it distinguish between harmless commensals and potentially harmful pathogens. This process is important for the development of a well-regulated immune response.
What is the MAC?
State the 3 MAIN pathways of activating the complement system.
The Membrane Attack Complex (MAC) is the final step in the activation of the complement system, a complex cascade of proteins that plays a crucial role in the innate and adaptive immune responses.
The complement system is activated through three main pathways:
*The classical pathway, the lectin pathway, and the alternative pathway.
Describe the classical pathway of activating the complement system.
The classical pathway is triggered by activation of the C1-complex.
The C1-complex is composed of 1 molecule of C1q, 2 molecules of C1r and 2 molecules of C1s, or C1qr2s2.
This occurs when C1q binds to IgM or IgG complexed with antigens.
A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed.
This also occurs when C1q binds directly to the surface of the pathogen.
Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r molecules. C1r is a serine protease.
They then cleave C1s (another serine protease).
The C1r2s2 component now splits C4 and then C2, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b).
C4b and C2a bind to form the classical pathway C3-convertase (C4b2a complex), which promotes cleavage of C3 into C3a and C3b.
C3b later joins with C4b2b to make C5 convertase (C4b2a3b complex).
Describe the Lectin pathway of activating the complement system.
Initiation: The lectin pathway is triggered by the binding of mannose-binding lectin (MBL), a pattern recognition molecule, to microbial carbohydrates (e.g., mannose) on the surface of pathogens.
Activation of MBL-Associated Serine Proteases (MASPs):
MBL binding activates MASP-1 and MASP-2, which then cleave complement proteins C4 and C2, forming the lectin pathway C3 convertase (C4bC2a).
Describe the Alternative pathway of activating the complement system.
- Spontaneous Hydrolysis of C3:
In the absence of external triggers, a small fraction of C3 molecules undergoes spontaneous hydrolysis (tick over) in the plasma, producing C3(H2O). - Formation of C3 Convertase: C3(H2O) is recognized by Factor B, and Factor B is then cleaved by Factor D into Ba and Bb. The resulting complex, C3(H2O)Bb, acts as the alternative pathway C3 convertase.
This complex is also known as a fluid-phase C3-convertase.
This convertase, the alternative pathway C3-convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b.
- We then have C3bBb which is the C3 convertase.
- Stabilization by Properdin: Properdin stabilizes the C3 convertase, preventing its rapid decay and amplifying the alternative pathway activation.
The addition of properdin forms the complex C3bBbP, a stable compound which can bind an additional C3b to form alternative pathway C5-convertase.
Describe the physiology of the complement system (MAC) as part of innate immunity.
- Activation of the Complement System:
The complement system is activated in response to various triggers, including the presence of pathogens, immune complexes, and damaged host cells.
Activation occurs through one of the three pathways, and each pathway leads to the formation of C3 convertases, which cleave the central complement protein C3 into C3a and C3b.
- Formation of C5 Convertase:
C3b, generated during the initial steps of complement activation, can bind to the surface of pathogens or target cells.
Additional complement proteins, including C5, are recruited to the surface bound C3b. This leads to the formation of the C5 convertase.
- Formation of the Membrane Attack Complex (MAC):
The C5 convertase cleaves C5 into C5a and C5b.
*C5a is an anaphylatoxin that induces inflammation and recruits immune cells.
*C5b initiates the assembly of the MAC by binding to the target cell membrane.
Polymerization of Complement Proteins:
C6, C7, C8, and multiple molecules of C9 are sequentially recruited and polymerize on the target cell membrane in a stepwise manner.
This assembly forms a transmembrane pore-like structure, creating a channel through the lipid bilayer of the target cell.
- Pore Formation and Lysis:
The completed MAC structure forms a pore on the target cell membrane. This pore disrupts the membrane integrity, leading to osmotic imbalance and cell lysis.
The lysis of the target cell is a potent mechanism for eliminating pathogens, damaged host cells, or other foreign entities.
- Release of Anaphylatoxins:
Throughout the complement activation cascade, the cleavage of certain complement proteins, such as C3 and C5, generates anaphylatoxins (C3a and C5a).
Anaphylatoxins contribute to the inflammatory response by inducing the release of histamine, chemotaxis of immune cells, and activation of phagocytes.
The adaptive immunity has memory, amplified response.
Describe adaptive immune response via the B cells
B- CELLS
1. Immunoglobulins (Antibodies): AGME
B-cells produce antibodies (immunoglobulins) as part of the adaptive immune response.
Antibodies recognize and bind to specific antigens (AG), marking them for elimination or neutralization.
- Produced in Bone Marrow (BM), Mature in Lymph Nodes (LN)
B-cells originate from stem cells in the bone marrow, where they undergo maturation.
Mature B-cells then migrate to secondary lymphoid organs, such as lymph nodes, where they encounter antigens and initiate immune responses.
- Responsible for Humoral Immunity (Passive or Active Immunity)
B-cells are central to humoral immunity, which involves the production of antibodies in response to extracellular pathogens (viruses, bacteria, toxins).
Humoral immunity can be achieved through natural exposure (active immunity) or by receiving pre-formed antibodies (passive immunity).
Describe adaptive immune response via the T cells
T-CELLS
- CD4 & CD8 (Cytotoxic) Cells
T-cells can be broadly categorized into CD4+ (helper) and CD8+ (cytotoxic) cells.
CD4+ T-cells assist in coordinating immune responses, while CD8+ T-cells are involved in directly killing infected or abnormal cells.
- Produced in Bone Marrow (BM), Mature in Thymus
T-cells, like B-cells, originate from bone marrow, but they undergo maturation in the thymus.
During maturation, T-cells develop specificity for antigens and gain immunocompetence.
- Responsible for Cell-Mediated Immunity
T-cells are crucial for cell-mediated immunity, which involves the direct action of immune cells against infected or abnormal cells.
CD8+ cytotoxic T-cells recognize and eliminate cells infected with intracellular pathogens.
State the 2 types of immunodeficiencies.
- Primary immunodeficiencies
- Secondary immunodeficiencies
What is primary immunodeficiency?
Primary immunodeficiency refers to a group of disorders characterized by defects or deficiencies in the components of the immune system that are present from birth (primary, inherent, or genetic).
These disorders result in impaired or absent immune function, making individuals more susceptible to infections and, in some cases, autoimmune conditions or malignancies.
Describe examples of primary immunodeficiency.
- B-cell deficiencies: recurrent bacterial infections
- T-cell deficiencies: recurrent fungal & virus infections
- Defects of phagocytosis: recurrent multiple abscesses.
- Disorders of the complement system: recurrent Neisseria infections.
- X-linked Agammaglobulinemia (XLA): A disorder where B-cells are unable to mature, resulting in a lack of immunoglobulins and increased susceptibility to infections.
- Chronic Granulomatous Disease (CGD): Characterized by defects in the ability of white blood cells to kill certain bacteria and fungi, leading to recurrent infections.
- Common Variable Immunodeficiency (CVID): Characterized by low levels of immunoglobulins (antibodies) and an increased susceptibility to infections.
