Immune System

Question 1

Innate Immunity

Answer 1

• Nonspecific immunity, defenses that are always active against infection (act near entry points into the body) but that lack the ability to target specific invaders.

• First Line of Defense: Skin provides physical barrier to pathogens and produces Defensins (antibacterial enzymes) and sweat (which has antimicrobial properties). Also included are mucous membranes of lungs, which are lined with cilia to trap particulate matter and pathogens and push them up to swallow or expel, and mucous membranes of eyes and oral cavity, which produce Lysozyme (nonspecific bacterial enzyme). Stomach secretes acid (eliminating most pathogens) and large bacterial population in gut outcompetes potential invaders (keeping them at bay).
• Complement: Antibacterial nonspecific proteins that can be activated through Classical Pathway (requires the binding of an antibody to a pathogen) or Alternative Pathway (does not require antibodies) to punch holes in bacterial cell walls, making them osmotically unstable.
• Interferons: Proteins released by virally infected cells that cause nearby cells to decrease translation of both viral and cellular proteins (to prevent viral replication), to decrease permeability of these nearby cells (to make it harder for virus to infect them), and to upregulate MHC I and MHC II molecules (to increase antigen presentation and detection of infected cells). Responsible for “flu-like” symptoms during viral infection (malaise, tiredness, muscle soreness, fever).
• Macrophages: Agranulocyte derived from blood-borne monocytes; can become Resident Population in tissue. Macrophage phagocytizes invader through endocytosis, digests it using enzymes, and presents bacterial antigens (pathogenic peptides) on its cell surface using MHC II. Also release Cytokines (chemical substances that stimulate inflammation and recruit additional immune cells to the area).
• Dendritic Cells: APC, presents antigens from pathogens or cancer cells to adaptive immune cells to trigger adaptive response. Macrophages and Dendritic Cells have Pattern Recognition Receptors (PRRs), like Toll-Like Receptors (TLRs), that are able to recognize the category of invader (bacterium, virus, fungus, parasite) to produce appropriate cytokines to recruit the right immune cells.
• Natural Killer (NK) Cells: Nonspecific lymphocytes that can detect downregulation of MHC expression as sign of viral infection or cancer and induce apoptosis in these virally infected or cancerous cells.
• Neutrophils: Phagocytes that targets bacteria either by using chemotaxis to follow bacteria or by detecting bacteria that have been Opsonized (marked with opsonins, like antibodies or complement proteins).
• Eosinophils: Involved in allergic reactions and parasitic infections; releases Histamine to trigger inflammatory response against extracellular pathogens (bacteria, fungi, parasites).
• Basophils and Mast Cells: Involved in allergic reactions; upon activation, release large amounts of Histamine, which causes inflammation and induces vasodilation and movement of fluids and immune cells (macrophages and neutrophils) from bloodstream into tissues.

Question 2

Adaptive Immunity

Answer 2

• Specific Immunity, defenses that are slow to act but that target pathogens with great specificity and maintain immunological memory of an attack to mount a faster attack in subsequent infections. Divided into Humoral Immunity (driven by B-cells) and Cell-Mediated Immunity (driven by T-cells).

• B-cells: Produced in and mature in Bone Marrow but are considered naive until activated in Lymph Nodes or Spleen. Generate Antibodies/Immunoglobulins.
• Antibodies can cause Opsonization (marking antigens with antibodies to help leukocytes detect and phagocytize them), Agglutination (clumping pathogens together to form large insoluble complexes for phagocytosis), Neutralization (inactivating pathogen’s ability to invade tissues).
• Antigen binding to cell-surface antibodies on B-cells triggers proliferation of Plasma Cells and formation of Memory Cells. Antigen binding to cell-surface antibodies on Mast Cells triggers Degranulation (exocytosis of Histamine to initiate inflammation).
• Antibodies are made up of two identical Heavy Chains and two identical Light Chains held together by disulfide linkages (formed by Cysteine residues) and noncovalent interactions. Antigen-binding region at end of Variable Domain at tip of Y that undergoes Hypermutation to bind only one specific antigenic sequence (B-cells that bind antigen with high affinity survive via Clonal Selection). Remaining part of antibody is Constant Domain and is the region that NK cells, macrophages, monocytes, neutrophils, and eosinophils have receptors for and that can initiate complement cascade.
• Antibody production is energetically expensive, so naive B-cells wait in lymph nodes and spleen for their particular antigen. Upon exposure to correct antigen, B-cell proliferates into Plasma Cell (produces large amounts of antibodies and aids slow Primary Response during first exposure to a particular antigen) and Memory B-cell (stored in lymph nodes and spleen and is responsible for rapid/robust Secondary Response upon reexposure to same antigen).
• T-cells: Produced in Bone Marrow and mature in Thymus, where they undergo Positive Selection (only those T-cells that can respond to antigens presented on MHC are allowed to survive) and Negative Selection (those T-cells that cannot respond to MHC or that are activated by self proteins undergo apoptosis); maturation of T-cells is facilitated by Thymosin (peptide hormone secreted by thymic cells).
• Mature T-cells leave thymus but are considered naive until activated in periphery. Upon exposure, T-cells undergo Clonal Selection, in which only those that bind a given antigen with the highest affinity proliferate.
• Helper T-cells (CD4⁺ T-cells): Coordinate immune response by activating macrophages and B-cells and by secreting chemicals known as Lymphokines, which recruit Plasma Cells, Cytotoxic T-cells, Macrophages and increases their activity. CD4⁺ T-cells respond to Exogenous antigens presented on MHC II molecules and are most effective against bacterial, fungal, and parasitic infections.
• Cytotoxic T-cells (CD8⁺ T-cells): Directly kill virally infected cells by injecting toxic chemicals into infected cell to promote apoptosis. CD8⁺ T-cells respond to Endogenous antigens presented on MHC I molecules and are most effective against viral and intracellular bacterial or fungal infections.
• Suppressor/Regulatory T-cells: CD4⁺ T-cells that help tone down immune response once infection has been adequately contained and that facilitate Self-Tolerance (turning off self-reactive lymphocytes to prevent autoimmune diseases).
• Memory T-cells: Generated from Primary Response and serves to carry out more robust/rapid Secondary Response upon reexposure to same antigen.

Question 3

Anatomy

Answer 3

• Bone Marrow: Site of Hematopoiesis (production of erythrocytes, leukocytes, and platelets). B-cells and T-cells produced here. B-cells mature in the bone marrow, but are considered naive (not yet exposed to an antigen) when they leave.
• Spleen: Site of leukocytes and platelets storage, erythrocytes recycling, blood/lymph filtration, and B-cell activation, turning B-cells into Plasma Cells that can produce antibodies as part of Humoral Immunity.
• Thymus: Site of maturation of T-cells, which coordinate immune system and directly kill virally infected cells as part of Cell-Mediated Immunity.
• Lymph Nodes: Site of lymph filtration, B-cell activation, and mounting of immune responses.
• GALTs: Tonsils and Adenoids in mouth, Peyer’s Patches in small intestine, and Appendix.

Question 4

Types of Leukocytes

Answer 4

• Granulocytes and Agranulocytes come from Hematopoietic Stem Cells. Names are based on presence or absence of Granules, which contain toxic enzymes and chemicals that are released by exocytosis and are effective against bacterial, fungal, and parasitic pathogens.
• Granulocytes: Neutrophils, Eosinophils, Basophils.
• Agranulocytes: Lymphocytes (B-cells and T-cells) and Monocytes (phagocytic cells in blood that become Macrophages in tissues; resident macrophages are called Microglia in CNS, Langerhans Cells in skin, Osteoclasts in bone).

Question 5

MHC

Answer 5

• MHC I: Used by all nucleated cells to present endogenous antigens; only cells infected with a virus or other intercellular pathogen should display nonself proteins and can be targeted by cytotoxic T-lymphocytes.
• MHC II: Used only by professional Antigen-Presenting Cells (Macrophages, Dendritic Cells, B-cells) to present exogenous antigens; pathogens from the environment are phagocytosed by APCs, processed, and displayed on MHC-II to activate both innate and adaptive immune responses.

Question 6

Self and Nonself

Answer 6

• Self-Antigens: Proteins and carbohydrates present on the surface of every cell of the body which signal to immune cells that the cell is not foreign and should not be attacked.
• Hypersensitivity Reactions: Autoimmunity and allergies.
• Autoimmunity: Occurs when the immune system fails to make the distinction between self and foreign and attacks cells expressing particular self antigens.
• Allergies: Occurs when the immune system misidentifies a foreign antigen as dangerous when it is not inherently threatening to human life and becomes overactivated when these antigens are encountered.
• Autoimmune reactions are prevented very early in T-cell and B-cell maturation processes. Negative selection of self-reactive T-cells occurs in thymus during education, and self-reactive immature B-cells are eliminated in bone marrow.
• Autoimmune diseases treated with Glucocorticoids (modified versions of cortisol), which have potent immunosuppressive qualities.

Question 7

Immunity

Answer 7

• Active Immunity: The immune system is stimulated to produce antibodies against a specific pathogen either by being exposed to this pathogen naturally via the environment or artificially via vaccines.
• Passive Immunity: Antibodies are transferred to the individual, such as across placenta during pregnancy or through breast milk during nursing.

Question 8

Lymphatic System

Answer 8

• Fats packaged into chylomicrons by intestinal mucosal cells enter Lacteals (small lymphatic vessels located at the center of each villus in the small intestine) for transportation. Lymphatic fluid carrying chylomicrons is called Chyle.
• B-cells proliferate and mature in the lymph nodes in collections called Germinal Centers, and lymph nodes are a place for antigen-presenting cells and lymphocytes to interact.