Immunology Fundamentals

• Blood components consist of plasma (liquid), erythrocytes (red blood cells), and leukocytes (white blood cells).
• The two types of immune responses are innate (quick and non-specific) and adaptive (slow, specific, and with memory).
• Adaptive immune responses take 7-10 days and require activation.
• Leukocytes (WBCs) include dendritic cells, which present antigens using MHC to activate naive T cells.
• Dendritic cells bridge the innate and adaptive immune systems.
• Myeloid cells are often involved in the innate response.
• Macrophages phagocytose and kill bacteria, alert the immune system, and aid tissue repair.
• Neutrophils phagocytose and kill bacteria and are the most abundant leukocyte in the bloodstream.
• Mast cells and dendritic cells reside in tissues.
• Dendritic cells phagocytose pathogens, migrate to lymph nodes, and activate adaptive immune responses.
• Monocytes reside in blood.
• Lymphocytes are often involved in the adaptive response.
• T cells (CTLs) kill virally infected cells.
• Helper T cells provide cytokines and signals to B cells, CTLs, and macrophages.
• B cells secrete antibodies into body fluids.
• Antibodies can kill bacteria, opsonize pathogens, and neutralize pathogens by binding to specific parts like viral surface proteins or toxins.
• All immune system cells derive from a hematopoietic stem cell (HSC) in the bone marrow, umbilical cord blood, and blood.
• HSCs are self-renewing and make up only 1% of bone marrow cells.
• Common lymphoid progenitor cells (CLP) produce lymphoid cell types.
• Common myeloid progenitor cells (CMP) produce myeloid cell types.
• Radiation can damage HSCs, CMPs, and CLPs by causing DNA damage and cell death.
• Radiated mice die within 10 days due to prevented production of RBCs, WBCs, and platelets.
• Infused hematopoietic systems allow radiated mice to survive, with HSCs restoring blood cells.
• Covering the bone and spleen prevents radiated mice from developing radiation syndrome.
• HSCs reside in the bone marrow cavity, circulate in the blood, and re-enter the bone marrow to restore HSCs.
• The primary lymphoid organs are the bone marrow and thymus (for T cells).
• Lymphocytes develop and mature in primary lymphoid organs.
• B cells develop in bone marrow.
• T cells start in bone marrow and migrate to the thymus.
• Secondary lymphoid organs include the spleen, lymph nodes, and gut-associated lymphoid tissues (GALT).
• GALT includes tonsils, adenoids, appendix, and Peyer's patches.
• Lymphocytes encounter and respond to pathogens in secondary lymphoid organs.
• The two circulatory systems are the blood circulatory system and the lymph circulatory system.
• The blood circulatory system moves blood throughout the body, including the spleen.
• The lymph circulatory system moves lymph fluid throughout the lymph nodes.
• The spleen and lymph nodes act as filters that trap pathogens for immune responses.
• The thoracic duct returns lymph fluid to the blood circulatory system.

Innate Immune Responses

• Pathogens have pathogen-associated molecular patterns (PAMPs).
• PAMPs are not found in multicellular hosts.
• PAMPs are present on numerous groups of pathogens and essential for microbe survival, so they do not undergo frequent mutations.
• Examples of PAMPs are LPS, peptidoglycan, and dsRNA.
• Pattern recognition receptors (PRRs) on cells like neutrophils, macrophages, and dendritic cells bind to PAMPs.
• The two main groups of cell-associated membrane PRRs are phagocytosis receptors and Toll-like receptors.
• Phagocytosis receptors trigger engulfment of pathogens.
• Toll-like receptors initiate intracellular signals upon binding to PAMPs.
• PAMP binding leads to cytokine release, MHC class II protein upregulation, and B7 co-stimulatory molecule upregulation.
• Two important types of proteins in innate responses are complement proteins and soluble PRRs.
• Soluble PRRs can activate complement.
• The complement system is a set of plasma proteins that attack extracellular pathogens via a cascade process.
• Complement proteins form a membrane attack complex with other proteins, opsonize pathogens, and promote inflammation.
• Complement activation pathways lead to C3 activation.
• The classical pathway involves antibody binding to a pathogen.
• The alternative pathway involves the spontaneous breakdown of C3.
• C3a stimulates macrophages to release TNF-alpha and contributes to inflammation.
• C3b acts as an opsonin to form C5 convertase.
• C5a stimulates mast cells to release histamine and contributes to inflammation.
• C5b initiates the formation of the membrane attack complex (MAC).

Levels of Defense

• The level of defense against infection is the overarching goal of the immune system.
• Anatomical and physiological barriers (skin, saliva, tears, stomach acid skin) are the first line of defense.
• The innate response starts in minutes and peaks in 2-3 days.
• The adaptive response is slow to start and reaches full activity in 7-10 days.
• Immediate innate responses involve preformed proteins and phagocytic cells already in tissues, examples are complement in blood and resident macrophages..
• The induced innate phase involves recruiting phagocytic cells from the bloodstream to the infection site and resident macrophages are responsible for this.
• Resident macrophages use Toll-like receptors and PAMPs to recognize bacteria and signal to recruit more phagocytes.
• Changes in blood vessel walls allow neutrophils and monocytes to enter the infection site, leading to the inflammatory response.
• Phagocytic cells migrate towards the bacteria, engulf it and kill it
• Inflammation can be caused by physical and chemical insults or invasion by microorganisms and eliminates 95% of infections.
• Acute inflammation is short in duration and primarily caused by the innate response whereas chronic inflammation lasts months to years and involves activated macrophages and T cells, often resulting in damage to healthy tissues.
• Resident macrophages and mast cells work as an early warning system against pathogens.
• The induced phase is characterized by mast cells releasing histamine and resident macrophages releasing proinflammatory cytokines.
• Histamine dilates local blood vessels, causing inflammation (pain, redness, swelling, increased temperature).
• Cytokines make endothelial cells leaky and sticky, leading to the recruitment of neutrophils and monocytes.
• Neutrophils and monocytes bind to adhesion molecules and roll on the blood vessel wall and squeeze (extravasate) and move into the tissue.
• Neutrophils, monocytes, and dendritic cells follow the IL-8 gradient to the infection site and begin to phagocytose bacteria.
• Monocytes mature into macrophages.
• Phagocytosis involves bacterium binding to a phagosome via phagocytic PRRs, engulfment into a phagosome, and fusion with a lysosome to become a phagolysosome.
• Phagolysosomes contain a highly acidic environment, activated proteases, nitric oxide, H2O2, and oxygen radicals.
• Destruction of pathogens occur in neutrophils and macrophages.
• Antigen presentation by MHC proteins to T cells occurs in dendritic cells

Antigen Processing and Presentation

• The major histocompatibility complex (MHC) displays peptides from self-proteins or pathogens.
• MHC class I proteins are expressed by all nucleated cells (except mature red blood cells); consists of a transmembrane alpha chain non-covalently associated with a beta2-microglobulin
• MHC class I peptide binding groove is within the alpha chain and binds peptides of 8-10 amino acids that derive from cytosolic, self, and viral proteins
• MHC class II proteins are expressed by antigen-presenting cells (dendritic cells, macrophages, and B cells) and commiunicate with the T cells to activate adaptive immune response.
• MHC class II consists of transmembrane alpha and beta chains
• MHC class II peptide binding groove is between the alpha and beta chains and binds peptides of at least 13 amino acids, which are derived from extracellular proteins
• MHC is polygenic, involving multiple genes that encode MHC molecules.
• Human MHC class I proteins include HLA-A, HLA-B, and HLA-C
• Human MHC class II proteins include HLA-DP, HLA-DR, and HLA-DQ
• MHC is polymorphic with many variants that exist in the population.
• Each MHC gene has many alleles (genetic variants) within the population.
• HLA proteins are co-dominantly expressed so that both alleles from your the mother and father are equally expressed in the phenotype
• Pros of MHC polymorphism allow cells to present many different peptides, activating the immune system and ensuring species survival.
• Cons of MHC polymorphism makes organ transplantation difficult due to immune rejection.
• Immunosuppressive medicines prevent the recipient's immune system from attacking the graft (host-graft disease).
• All proteins have half-life -> need to make a new protein to replace the old one
• The level of gene expression can be controlled when cells receive signals from the environment (cytokines, receptor/ligand binding)

Controlling Gene Expression

• Induce: initiate transcription of the gene
• Up-regulate: increase transcription -> more protein
• Down-regulate: decrease transcription -> less protein
• Antigen processing is the degradation of proteins into peptide fragments.
• Antigen presentation is the binding and display of the antigen as a peptide fragment bound to mHC proteins on the surface of a cell.
• MHC class I proteins are peptide loaded by the endogenous pathway

1. Cytosolic proteins are degraded into peptides by proteasome in cytoplasm
2. Peptides are transported into the lumen of ER by TAP
3. Newly made MCH class I associates with beta2-microglobulin
4. Peptides bind to MHC class I in the lumen of the ER
5. Leaves ER and moves through Golgi apparatus
6. MCH class 1 peptide complex are displayed on the cell surface for ~24 hours before being internalized and replaced

• MHC class II proteins are peptide loaded by the exogenous partway

1. protein/pathogen is internalized by APC (antigen-presenting cell)
2. endosome/phagosome fuses with lysosome -> protease degrades proteins into peptides
3. Newly made MHC II associates with the invariant chain , which blocks the peptide binding site
4. Leaves the ER in a vesicle and proceeds through the Golgi apparatus
5. The invariant chain gets partially digested and leaves a small protein called CLIP in the peptide binding site
6. The peptide vesicle fuses with the MHC II vesicle
7. CLIP is removed and replaced with a peptide
8. MHC 2 peptide complex is displayed on the cell surface for ~48 hours

Cross-Presentation

• Cross-presentation of dendritic cells: blend of both exogenous and endogenous pathways.
• Dendritic cell display peptides on both MHC class I and MHC class II and can simultaneously activate both CTLs and Thelper cells respectively
• Involves, first, the exogenous pathway part: when a virus particle is phagocytosed and digested by proteases.
• Also, the dendritic cell receives a signal that it needs to do cross-presentation
• The "change-over” event: is where some of the fragments escape into the cytoplasm and are degraded by proteasome -> produce peptide
• Followed by endogenous pathway part: where peptides are loaded onto MHC class I
• And also, peptides that are further processed in the phagolysosome which continue to be leaded onto MHC class II

Dendritic Cells

• Dendritic cells: most important antigen presenting cell of naive T cells
• Dendritic cells are derived from both common myeloid precursors and common lymph precursors
• Dendritic cells constitutitively express MHC class I, MHC class II and the co-stimulatory protein B7.
• Can also do cross-presentation

T Cells and Adaptive Immunity

• T cells include CD4 helper cells that recognize peptides presented on MHC class II proteins.
• T cells include CD8 killer cells (CTL) that recognize peptides presented on MHC class I proteins
• T cell receptor TCR is a membrane-bound protein compound of two different polypeptides (alpha and beta chains) joined by di-sulfate band
• Alpha beta TCR is an antigen binding site that recognizes a comples of MHC and peptide and therefore antigen recognition
• A co-receptor (CD4 or CD8) stregthens the interaction between the antigen-presenting cell (APC) and T helper cell
• CD3 interacts with the signalling proteins that relay a signal to the nucleus -> T cell would undergol clinical expansion (proliferate), then differentiate into different subsetsof T cell such as CTL or helper T cell
• Since T cells can't recognize soluble antigens -> can be activated when antigens is presented
• The variabl region has some variability of amino acid sequence in alpha and beta chains -> highly selective
• Whereas the conserved region is the same for all TCRs

Development and Selection of T Cells

• Development of T cells -> interaction of MCH determines wherther a T cell will be TCL or Helper T cell
• In the Bone Marrow, HSC -> CLP -> T cell precursor with no TCR expresses yet
• Later, in the Thymus, the T cell precursor transitions into a thymocyte (TCR+CD4-CD8-) progresses to a thymocyte ( TCR+CD4+CD8+)
• Following positive selection, it becomes CD4+CD8+
• Following negative selection, it becoms, CD4+CD8-or CD4-CD8+-> a mature T cell
• If positive or negative selection fail, -> apoptosis occurs
• Since only the cells preformed a task correctly can get the survivalsignal
• Positive selection involves identifying developing T cells that have TCRs that can bind MHC + self peptide weakly; graded by thymic cortical epithelial cells
• Interacts with MHC but is too weak to trigger activation of allinfity
• Finds potentially useful T cells
• Negative selection invloves identifying developing T cells that bind MCH + self peptide too tightly
• This prevents autoimmune disorder -> not self-reactive (high affinity)
• Regular negative selection: Graded by bone marrow-derived antigen-presentation cells in the Thymus -> normal proteins from common cell types AIRE-mediated neagtive selection: the autoimmune regulartator (AIRE) gene is expressed in Thymic medullary epithelial cells-> issue-restricted antigens found in specific organs (e.g pancrease, liver and brain)
• When positive and negative selection are complete
• Less than 5% of candidate thymocytes pass positive and negative selection because most fail in the positive selection to
• The point is to keep the thymocytes potenially useful

T Cell Activation

• Activation of the T-Cell needs exactly 3 signals because if it does not, then it can potentially be dangerous to health, like autoimmune disorder or excessiveimmune response
• Signal 1 (from APCs) is the TCR MHC interaction. Can occur when, 1) TCR binds to hMHC peptide complex that is complementary to TCR and 2) CD4 or CD8 binds to a conserved region of the MHC on APC, whereCD3 is activated and delivers signal 1 to the nucleus
• Signal 2 occurs from APCs, particularly as col-stimulatory signals. Where the CD28 binds of T cell binds to the B7 of the APC ->. Signal 1 and 2 allow the Thell to start making IL-2
• And a further signal (signal 3) occurs where they get cytokine signals
• Then IL-2 becomes autocrine, where, T cell secretes LL-2 into extracellular enviroment LL-2 binds to the ll-2 receptor on the T cell surface. Binding of L-2 to L-2R triggers signalling event->. proliferation and differentiation
  • As, for example, CD4 T cell-> CD4 effector cell and CD4 memory cell , but CD8
• Note that there is adifference autocrine systems of CD4 and CD8, where CTLs would need to get extra IL-2 made by TheHelper cells ->. For T helper cells, dendritic cells can provide part of sgnal 3 by providing acditional cytokines -> incluces the info about the type of infection and what type of help the
• There are Types of Antigen-presenting cells(APCs): -The first and best APCs are Dentritic cells as they are the best and only APCs for activation of naive T cell due, 1) to the Large surface area, and ability the up-regulate MHC I and I co-stimulatory molecule B7 when travelling to the lymph node, 2) the they Engulf the pathogen at the site of infection and migrate to the nearest lymph node to activate Thells,
  • Furthermore they can also pass theinfo of what the pathogen is and what type of immune response is needed
  • But whereas, Macrophage can engulf the pathogen but don't migrate to the neares lymph node - Because of this, Macrophage present antigens T cells that were already activated (do not primarily activate naive T cells) Since Some pathogens have mechanism to inhibit macrophages, preventing them from killing the engulfed -> The cells canenhance macrophage ability to overcome this
• Since B- cells, donot activate The cells
• How ever, by By binding.The cells, B cells can make high atfinity, class-switched Antibodies And develop memory 5 cells Otherwise, B- cells would make low affinity Ig Mand no memory 5 cell
• There are Treulatory cells ( Tregs) that can, by themselves, suppress self-realive T cells _ Tregs prevent autoimmone responsess by shutting down self-realive Teells

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Chapter 5: B Cells

B cells are part of adaptive immune system specifically as B-cells

• B cells' developmentcan be tracked with cell receptor such as immunoglobulin(Ig).

• in the the morrow HSC-> CLP-> B cell precursor (g)->mmature cel -> mature cell

• Because BCR: consists of variable regionand constant region. Variable region consists heavy.and light chain
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• There are mmunoglobus Ig MigD ga land gE
• Expect lgd al can be membrane bound or secreted.
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• the chainhas

Chapter 7: Antibody Structure and Function

• Antibodies are essential for immune process as they are the building blocks for defense
• The are Y-shaped and have heavy chains and light chains
• Have globular Ig domains: a compact, folded structure found in antibodies and manyimmune-related proteins. Consists of beta barrel made from 2 anti-parallel beta sheets
• Differences in the variable region are mostly in the hypervariable regions (CDRs)
• An antigen binding site is made up of 6 CDRs (3 from each chain)

IgM antibodies

• The differences between The four IgM antibodies is that IgM(Human)recognizes rabies visus
• As where IgM recognizes SARS-CoV-2, and IgM and also recognizes SARS-CoV-2,but IgM4(cog)recognizes rabies virus

Isotype of Antibodies

• Some are transfusion of antibodies that can have both
• Same species

• constant region are identical

• Can transfuse antibodies from one from one person from another
• Ex convalescent plasma (antibodiesfrom recovered patients used to treatnfections) and intravenousimmunoglobulin(pooled antibodies form heavy donors for immunodeficiency patients)
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Test your knowledge of immunology with these flashcards. Review blood components, immune responses, leukocytes, and antigen-presenting cells. Understand the differences between innate and adaptive immunity.