Immune Response and Vaccination

Mechanism Behind Vaccination

• Affinity maturation drives weak naive B cells to undergo rearrangement and extensive hypermutation to eventually secrete high-affinity IgG.
• Clonal selection occurs in lymph node follicles, including cervical lymph nodes, thoracic duct, lymphatics of the mammary gland, thymus, axillary lymph nodes, cisterna chyli, spleen, lumbar lymph nodes, and lymphatics of the upper and lower limbs.

Affinity Maturation in B Cells

• A massive repertoire of naive B cells is generated stochastically before birth, each with a unique B cell receptor.
• B cells encounter antigens in the lymph nodes, and an antigen expands a small number of B cell clones with receptors that weakly bind the antigen.
• Somatic hypermutation of the Ig gene results in some clones with higher antigen receptor affinity, and successive rounds of this process lead to mature B cells secreting soluble IgG.
• Some B cells reside in lymph nodes as long-term memory cells.

Tetanus Case Study

• Clostridum tetani is a common soil bacterium that produces Tetanus Toxin (TT), a neurotoxin that binds to the presynaptic membrane of the neuromuscular junction, causing spastic paralysis.

Thymus and T Lymphocytes

• The thymus is a site for immature lymphocytes from the bone marrow to mature.
• Ancient transposase is still present in our genome and is called RAG1 and RAG2 (recombination activation genes).
• Recognition sequences are located at the ends of all Ig and TcR gene segments.

Adaptive Immunity

• Adaptive immunity has memory and changes with time and persistence of antigen.
• A secondary response is stronger and more rapid than the naive response, which is the basis for vaccination.

Primary and Secondary Responses to Vaccination

• The first immunization with an antigen results in a rise in antigen-specific low-affinity IgM in the blood, peaking at about 2 weeks post-immunization, but then diminishing rapidly.
• The second and third immunizations (boosters) generate a rapid and intense burst of antigen-specific high-affinity IgG that lasts for a month or sometimes years.

Properties of Vaccines

• The best vaccines are inactive variants of bacterial toxins that rapidly produce high-affinity neutralizing IgG that binds to the toxin before it binds to its target receptor.

Transposons and Transposase

• Transposons are bits of DNA that have the ability to move themselves from one location to another location.
• Transposons have recognition DNA sequences at their ends.
• Transposase is an enzyme that cuts, inserts, and reinserts transposons, working on the recognition sequences on the transposons.

Lymphatic System

• The lymphatic system includes lymph nodes, lymphatics, thymus, and spleen.

MHC Polymorphism and Autoimmune Disease

• MHC polymorphisms are strongly linked to many autoimmune diseases, including Addison's disease, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and ankylosing spondylitis.
• The MHC locus is the only polymorphic part of the entire genome, making it strongly associated with autoimmune diseases.

Cellular Immunity

• Cellular immunity is regulated by MHC, a set of highly polymorphic genes coding for a group of membrane molecules called HLA in humans.
• T cell receptor (TcR) is an Ig-like membrane molecule, and its gene locus is segmented and undergoes rearrangement.

Graft Rejection and Tissue Transplant

• The experiment using congenic strains of mice showed that viral immunity requires both self MHC and the foreign antigen - MHC restriction.
• MHC polymorphism makes tissue transplant difficult.

CD4 and CD8

• CD4 and CD8 are accessory molecules associated with the T cell receptor, responsible for intracellular signaling through associated tyrosine kinases.

Allergy, Hypersensitivity, and Review

• Allergy is the most common form of immune disorder, affecting 30% of people.
• Hives (urticaria) is caused by the release of histamine into the tissue from mast cells in the skin.
• Oedema (swelling) is caused by leakage of fluid into the spaces between cells.
• Anaphylaxis and anaphylactic shock are serious consequences of allergic reactions.

Mechanism Behind Vaccination

• Affinity maturation drives weak naive B cells to undergo rearrangement and extensive hypermutation to eventually secrete high-affinity IgG.
• Clonal selection occurs in lymph node follicles, including cervical lymph nodes, thoracic duct, lymphatics of the mammary gland, thymus, axillary lymph nodes, cisterna chyli, spleen, lumbar lymph nodes, and lymphatics of the upper and lower limbs.

Affinity Maturation in B Cells

• A massive repertoire of naive B cells is generated stochastically before birth, each with a unique B cell receptor.
• B cells encounter antigens in the lymph nodes, and an antigen expands a small number of B cell clones with receptors that weakly bind the antigen.
• Somatic hypermutation of the Ig gene results in some clones with higher antigen receptor affinity, and successive rounds of this process lead to mature B cells secreting soluble IgG.
• Some B cells reside in lymph nodes as long-term memory cells.

Tetanus Case Study

• Clostridum tetani is a common soil bacterium that produces Tetanus Toxin (TT), a neurotoxin that binds to the presynaptic membrane of the neuromuscular junction, causing spastic paralysis.

Thymus and T Lymphocytes

• The thymus is a site for immature lymphocytes from the bone marrow to mature.
• Ancient transposase is still present in our genome and is called RAG1 and RAG2 (recombination activation genes).
• Recognition sequences are located at the ends of all Ig and TcR gene segments.

Adaptive Immunity

• Adaptive immunity has memory and changes with time and persistence of antigen.
• A secondary response is stronger and more rapid than the naive response, which is the basis for vaccination.

Primary and Secondary Responses to Vaccination

• The first immunization with an antigen results in a rise in antigen-specific low-affinity IgM in the blood, peaking at about 2 weeks post-immunization, but then diminishing rapidly.
• The second and third immunizations (boosters) generate a rapid and intense burst of antigen-specific high-affinity IgG that lasts for a month or sometimes years.

Properties of Vaccines

• The best vaccines are inactive variants of bacterial toxins that rapidly produce high-affinity neutralizing IgG that binds to the toxin before it binds to its target receptor.

Transposons and Transposase

• Transposons are bits of DNA that have the ability to move themselves from one location to another location.
• Transposons have recognition DNA sequences at their ends.
• Transposase is an enzyme that cuts, inserts, and reinserts transposons, working on the recognition sequences on the transposons.

Lymphatic System

• The lymphatic system includes lymph nodes, lymphatics, thymus, and spleen.

MHC Polymorphism and Autoimmune Disease

• MHC polymorphisms are strongly linked to many autoimmune diseases, including Addison's disease, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and ankylosing spondylitis.
• The MHC locus is the only polymorphic part of the entire genome, making it strongly associated with autoimmune diseases.

Cellular Immunity

• Cellular immunity is regulated by MHC, a set of highly polymorphic genes coding for a group of membrane molecules called HLA in humans.
• T cell receptor (TcR) is an Ig-like membrane molecule, and its gene locus is segmented and undergoes rearrangement.

Graft Rejection and Tissue Transplant

• The experiment using congenic strains of mice showed that viral immunity requires both self MHC and the foreign antigen - MHC restriction.
• MHC polymorphism makes tissue transplant difficult.

CD4 and CD8

• CD4 and CD8 are accessory molecules associated with the T cell receptor, responsible for intracellular signaling through associated tyrosine kinases.

Allergy, Hypersensitivity, and Review

• Allergy is the most common form of immune disorder, affecting 30% of people.
• Hives (urticaria) is caused by the release of histamine into the tissue from mast cells in the skin.
• Oedema (swelling) is caused by leakage of fluid into the spaces between cells.
• Anaphylaxis and anaphylactic shock are serious consequences of allergic reactions.

Circulation of Blood

• The heart pumps blood to the lungs through the pulmonary artery, where it is oxygenated and then returns to the left atrium through the pulmonary vein.
• Blood is circulated through the body via the left ventricle, which pumps blood out through the aorta and into the arterial system.
• The pressure of arterial blood is high due to the elastic vessel walls containing smooth muscle, which allows the heart to pump blood efficiently.
• Venous pressure is lower because veins are not elastic, and the pressure is maintained by the heart's pumping action.

Blood Composition and Function

• Myeloid cells are responsible for innate immunity, while lymphoid cells participate in adaptive immune responses.
• Proteins present in blood include:
  • Albumin: most abundant protein, providing osmotic pressure and maintaining hypertonicity
  • Hemoglobin: component of RBCs that carries oxygen
  • Fibrinogen: forms blood clots, constitutes 7% of blood
  • Immunoglobulins: antibodies
• Lipids in blood are bound in lipoproteins: HDL, LDL, and VLDL
• Other components of blood include:
  • Electrolytes (salts and minerals)
  • Vitamins
  • Hormones
  • Glucose

Regulation of Blood pH

• Blood pH is tightly maintained at 7.4, with a variance of more than 0.2 resulting in severe stress, acidosis, or alkalosis.
• Blood pH is effectively buffered by albumin, phosphate, bicarbonate, creatinine, and other compounds.

Centrifugation and Separation of Blood

• Centrifugation separates blood into three components:
  • Packed RBCs (approx. 40-45%)
  • Buffy coat (approx. 10%) containing white cells
  • Plasma (approx. 50%) containing dissolved substances and formed elements
• Plasma contains fibrinogen, while serum is blood without fibrinogen, essentially plasma without fibrinogen.
• Serum electrophoresis separates serum proteins into 5 major fractions: albumin, α1, α2, β, and γ fractions.

Blood Proteins and Their Roles

• The five major proteins in blood are:
  • Albumin: maintains colloidal osmotic pressure, binds and transports small molecules and hormones
  • Fibrinogen: forms blood clots through the coagulation cascade
  • Immunoglobulins (Ig): aka antibodies, participate in immune responses

Leukocytes and Haematopoiesis

• Natural Killer cells attack infectious microbes and spontaneously arising tumour cells
• Granular leukocytes: neutrophils, eosinophils, basophils
• Agranular leukocytes: lymphocytes, monocytes

Haematopoiesis

• Haematopoietic stem cells (HSC) are found mainly in the bone marrow
• HSC is characterized by a CD34 cell surface marker antigen
• HSC is relatively rare (about 1 in 10,000 white cells are CD34+)
• Multipotential hematopoietic stem cells can be saved and stored in liquid nitrogen for future use
• CD34+ is a surface antigen marker on HSCs
• Anti-CD34 antibody can select and concentrate HSCs from blood prior to a bone marrow transplant

Leukemia Treatment

• In adult patients, HSC is isolated using a monoclonal antibody with a fluorescent tag or magnetic bead that binds to the CD34+ antigen
• The patient is then treated with radiation, and the isolated CD34+ cells are transplanted back into the patient

Haematopoiesis and Cell Development

• CD34+ HSC gives rise to myeloid or lymphoid progenitors
• Myeloid progenitors can give rise to erythrocytes, platelet-producing megakaryocytes, mast cells, or myeloblasts
• Myeloblasts further differentiate into either neutrophils, basophils, eosinophils, or monocytes
• Lymphoid progenitors differentiate into B or T lymphocytes
• Immature T lymphocytes differentiate into CD4 or CD8

Factors that Drive Haematopoiesis

• GM-CSF (granulocyte macrophage colony-stimulating factor) stimulates the production of neutrophils, eosinophils, basophils, and monocytes
• EPO (erythropoietin) drives the production of erythrocytes
• G-CSF (granulocyte colony stimulating factor) stimulates the production of granulocytes and matures neutrophils

Hemoglobin and Oxygen Transport

• Hemoglobin is a major protein in RBCs and constitutes 96% of the RBC's dry weight
• Each hemoglobin molecule contains 4 lobes, each containing a haem
• Gas exchange occurs in the hemoglobin of RBCs through the binding of oxygen to the haem

MHC and Autoimmune Diseases

• MHC polymorphism is strongly linked to many autoimmune diseases
• Diseases associated with MHC polymorphism include: Addison's disease, type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and ankylosing spondylitis

Cellular Immunity

• Cellular immunity is regulated by MHC, a set of highly polymorphic genes coding for a group of membrane molecules called HLA in humans
• T cell receptor (TcR) is an Ig-like membrane molecule that undergoes rearrangement
• MHC restriction implies that viral immunity requires both self MHC and the foreign antigen

Allergy and Hypersensitivity

• Allergy is the most common form of immune disorder, affecting 30% of people
• Hives/urticaria is caused by the release of histamine into the tissue from mast cells in the skin
• Oedema/swelling is caused by leakage of fluid into the spaces between cells
• Anaphylaxis and anaphylactic shock are serious consequences of allergic reactions