Advanced Molecular Cell Biology - Immunology I
Definition of Immunity
Definition of Immunity: Immunity is defined as the state of being insusceptible or resistant to a noxious agent or process, specifically focusing on pathogens or infectious diseases.
Targets of the Immune System (Pathogens):
Bacteria.
Fungi.
Parasites.
"Foreign bodies" and "Foreign" tissues.
"Unwanted" cells (including cells undergoing necrosis, apoptosis, or cancerous transformation).
The First Lines of Defence
The first lines of defence consist of physical and chemical barriers that are always active and prepared to defend the body from infection.
Skin:
The largest organ in the human body.
Functions as a primary physical barrier.
Maintains its own microbiome consisting of "friendly" bacteria that occupy niches to prevent pathogenic colonization.
The lining of the gut is an epithelium that also serves barrier functions.
Secretions (Tears, Mucus, and Saliva):
Protect "openings" or potential entry points for pathogens.
Contain antimicrobial peptides known as defensins.
Contains enzymes such as lysozyme (found in tears) which digest bacterial cell walls.
Mechanical action: Pathogens are flushed out of the body or into the stomach to be killed.
The Respiratory System (Cilia):
The windpipe is lined with fine hairs called cilia.
Cilia move mucus and trapped particles (bacteria, dust, or smoke) away from the lungs.
Cystic Fibrosis Case Study: Caused by a mutation in a chloride ion channel, resulting in thickened mucus that cilia cannot move, leading to chronic lung infections.
Chemical and Biological Barriers:
Stomach Acid: Parietal cells secrete , lowering the pH to activate proteases like pepsin, which kills pathogens.
Urine Flow: Regularly flushes pathogens from the bladder and urethra.
The Microbiome: Naturally occurring bacteria in the gut, skin, mouth, and vagina act as competition against pathogens. The use of antibiotics or anti-bacterial soaps can disrupt this microbiome and open areas for colonization.
Innate Immunity: Detection and Signaling
When a pathogen breaches the first line of defence, the innate immune system must distinguish "self" from "non-self."
Recognition Patterns:
PAMPs (Pathogen-Associated Molecular Patterns): Molecular structures unique to pathogens. Examples include:
Lipopolysaccharides (LPS): Components of Gram-negative bacterial cell walls.
Formylated-methionine: An amino acid used only by bacteria, not eukaryotes.
DAMPs (Damage-Associated Molecular Patterns): Used to identify damaged "self" cells.
Toll-like Receptors (TLRs):
The largest family of receptors for detecting PAMPs.
There are known TLRs in humans.
Highly expressed by macrophages, dendritic cells, and neutrophils.
Signaling Cascade: TLR binding triggers a molecular signaling cascade through downstream effectors like Jun/Fos transcription factors and NFkB. This leads to changes in gene expression that drive the immune response.
Blood Composition and Leukocytes
Quantitative Data:
Adults contain approximately litres of blood.
Blood is composed of roughly (35 trillion) cells.
Bone marrow produces roughly (500 billion) new blood cells per day, which is approximately (2.4 million) cells per second.
Cell Types (Leukocytes/White Blood Cells):
Myeloid Cells: Generally provide innate protection.
Lymphoid Cells: Generally generate adaptive immunity.
Erythrocytes: Red blood cells (majority of cells) transporting .
Thrombocytes: Platelets.
Innate Immune Response and Inflammation
Activation of the innate immune system by TLRs and other receptors triggers localized and systemic responses.
Inflammation:
Characteristics: Pain, redness, heat, and swelling.
Mechanism: Local blood vessels dilate and become permeable. Endothelial cells lining the capillaries become "sticky," allowing white blood cells to stop moving and migrate into the tissue.
Cytokines: Pro-inflammatory molecules such as prostaglandins, histamines, and other cytokines are released.
Fever:
Inhibits the proliferation of pathogens.
Speeds up the chemical reactions used by antimicrobial peptides and the complement cascade.
Systemic Risk (Sepsis/Shock): A systemic immune response can cause a "cytokine storm." This leads to a loss of plasma volume (leakiness), a crash in blood pressure, and organ failure (shock).
Phagocytic Specialized Cells
Neutrophils:
Abundant in blood but not typically in tissues.
Short-lived and highly phagocytic.
Migrate to infection sites; they are the primary component of pus in wounds or spots.
Macrophages:
Long-lived "professional" phagocytes.
Abundant in areas likely to be exposed to pathogens (airways, gut).
Derived from monocytes.
Eosinophils:
Specialists in attacking objects too large for phagocytosis, such as parasitic worms.
Linking Innate and Adaptive Immunity
Dendritic Cells (DCs) act as the bridge between the two systems.
DCs are specialized phagocytic cells derived from monocytes.
They express a variety of recognition receptors (TLRs).
They phagocytose pathogens and cleave them into peptides.
These peptides are bound to MHC (Major Histocompatibility Complex) proteins on the cell surface.
DCs migrate to lymphoid tissues (e.g., lymph nodes) to activate and stimulate lymphocytes of the adaptive immune system.
Adaptive Immunity Foundations
Adaptive immunity generates highly specific responses to a vast range of pathogens and toxins but must avoid targeting "self" molecules.
Primary Lymphoid Organs: Thymus and bone marrow (where lymphocytes develop).
Secondary Lymphoid Organs: Lymph glands/nodes and the spleen (where lymphocytes are exposed to foreign antigens).
B-cells (B-lymphocytes):
Develop in the Bone marrow.
Differentiate into plasma cells that secrete soluble immunoglobulins (antibodies).
Antibodies make up approximately of the proteins in the plasma.
T-cells (T-lymphocytes):
Progenitors move from bone marrow to the Thymus to mature.
Mediate the cellular immune response.
Natural Killer (NK) Cells:
Lymphoid cells that are considered part of the innate response.
Defend against foreign cells and autologous cells under stress (infection or tumor transformation).
Subtypes of T-cells
Cytotoxic T-cells: Directly kill infected host cells.
Helper T-cells: Activate macrophages, dendritic cells, B-cells, and cytotoxic T-cells via cytokines and co-stimulatory surface proteins.
Regulatory T-cells: Inhibit the function of helper, cytotoxic, and dendritic cells to prevent over-activation.
Dynamics of the Adaptive Response
Clonal Selection and Expansion:
The body contains a randomly generated "library" of dormant lymphocytes.
When an antigen is presented (e.g., by DCs), lymphocytes with high binding affinity become activated.
Activation leads to proliferation (clonal expansion) and differentiation into effector cells.
Immunological Memory:
Subsequent encounters with the same antigen stimuate memory cells created during the first encounter.
The Second Response: Has a shorter lag time and is significantly stronger than the first.
This is the principle behind booster vaccinations and combined vaccines like the MMR.
Immune Tolerance
Immune tolerance is the process by which the adaptive immune system learns to ignore "self" antigens.
Transplantation Experiments:
Tissues transplanted between adults are rejected by T-cells.
Tissues transplanted into a newborn host are accepted as "self." Continued transplants from the same source later in life will also be accepted.
Example: A brown mouse skin graft survives on a different host if the host was injected with the brown mouse's bone marrow as a pup.
Genetic Experiments on Tolerance:
Knockout Experiment: If a gene for a "self" protein is knocked out and later reintroduced to the adult, the body mounts an immune response because it never "learned" the protein was self.
Removal Experiment: If a "self" protein is removed from an adult and reintroduced months or years later, the immune system may mount an attack, suggesting the system can "forget" self-recognition if the antigen is absent for long periods.